Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus Candida albicans
Open accessAbstract
Candida albicans is an opportunistic yeast and the major human fungal pathogen in the USA, as well as in many other regions of the world. Infections with C. albicans can range from superficial mucosal and dermatological infections to life-threatening infections of the bloodstream and vital organs. The azole antifungals remain an important mainstay treatment of candidiasis and therefore the investigation and understanding of the evolution, frequency and mechanisms of azole resistance are vital to improving treatment strategies against this organism. Here the organism C. albicans and the genetic changes and molecular bases underlying the currently known resistance mechanisms to the azole antifungal class are reviewed, including up-regulated expression of efflux pumps, changes in the expression and amino acid composition of the azole target Erg11 and alterations to the organism’s typical sterol biosynthesis pathways. Additionally, we update what is known about activating mutations in the zinc cluster transcription factor (ZCF) genes regulating many of these resistance mechanisms and review azole import as a potential contributor to azole resistance. Lastly, investigations of azole tolerance in C. albicans and its implicated clinical significance are reviewed.
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TL;DR
This review summarizes the molecular and genetic mechanisms of azole resistance in *Candida albicans*, including efflux pump overexpression, Erg11 target alterations, sterol biosynthesis changes, aneuploidy/loss of heterozygosity, azole import, Hsp90, biofilms, and azole tolerance. It reports that overall fluconazole resistance in *C. albicans* remains relatively low but can be higher in specific settings such as HIV/AIDS-associated oropharyngeal candidiasis.
Key findings
- Azole resistance mechanisms include upregulated efflux pumps (Cdr1/Cdr2 via Tac1 gain-of-function; Mdr1 via Mrr1 gain-of-function), Upc2-driven *ERG11* overexpression, *ERG11* mutations, *ERG3* defects/alternative sterol biosynthesis, aneuploidy/loss of heterozygosity, and possibly reduced azole import.
- Reported fluconazole resistance rates vary: overall as high as 3.5% (CLSI MIC ≥8 mg/L); 12%–22% in North American oral candidiasis HIV/AIDS patients; ARTEMIS found 1.4% of *C. albicans* isolates fluconazole resistant, with 63.6% of those cross-resistant to voriconazole; SENTRY 2013 reported 0.4% fluconazole and 0.3% voriconazole resistance in *C. albicans*.
- Gain-of-function mutations in zinc cluster transcription factors Tac1, Mrr1, and Upc2 are key drivers; evidence for other ZCFs such as Mrr2 is contradictory. Hsp90, biofilms, and tolerance (fraction of growth and supra-MIC growth) contribute to drug failure; higher FoG/SMG were associated with persistent candidemia despite susceptible MICs.
- Tetrazoles VT-1161 and VT-1598 show activity against azole-resistant *C. albicans*; VT-1598 retained activity against isolates with known resistance mechanisms, while VT-1161 MICs increased in isolates with increased efflux pump expression and azole target mutations.
Methods
- Narrative review; no primary experimental design, sample, or statistical analysis is reported.
- Synthesizes published literature on *C. albicans* azole resistance epidemiology, treatment, molecular mechanisms, and tolerance; no systematic search or inclusion criteria are described.
Limitations
- Paper-stated limitations: Not stated in the paper.
- Evident from the text: narrative review without systematic search/inclusion criteria or quantitative synthesis; reliance on cited studies with varying resistance definitions/breakpoints (e.g., fluconazole resistance defined as MIC ≥8 mg/L versus >4 mg/L in one Danish study) and unresolved contradictory findings (e.g., *MRR2* mutations).
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- Premisecitation§ Introduction
In North American oral candidiasis (HIV/AIDS-positive) patients, the prevalence of fluconazole-resistant C. albicans isolates was found to be between 12% and 22%.
“This has occurred with greatest frequency in the setting of patients suffering from HIV/AIDS during treatment for oropharyngeal candidiasis, where the prevalence of fluconazole-resistant C. albicans isolates in North American oral candidiasis (HIV/AIDS-positive) patients was found to be between 12% and 22%.38–42”
Quote in the paperNot a substantial claim0 of 5 sources checked- cites [38] Martins, 1998, Declining rates of oropharyngeal candidiasis and carriage of Candida albicans associated with trends toward reduced rates of carriage of fluconazole-resistant C. albicans in human immunodeficiency virus-infected patients, Clin Infect Dis source
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- cites [39] Martins, 1997, Point prevalence of oropharyngeal carriage of fluconazole-resistant Candida in human immunodeficiency virus-infected patients, Clin Infect Dis source
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- cites [40] Sangeorzan, 1994, Epidemiology of oral candidiasis in HIV-infected patients: colonization, infection, treatment, and emergence of fluconazole resistance, Am J Med source
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- cites [41] Sanglard, 2002, Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences, Lancet Infect Dis source
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- cites [42] Masia Canuto, 2000, Determinants for the development of oropharyngeal colonization or infection by fluconazole-resistant Candida strains in HIV-infected patients, Eur J Clin Microbiol Infect Dis source
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- Premisecitation§ Introduction
With respect to CLSI clinical breakpoints, fluconazole resistance, defined as MIC values ≥8 mg/L for C. albicans, has been reported overall to be as high as 3.5%.
“With respect to CLSI clinical breakpoints, fluconazole resistance, defined as MIC values ≥8 mg/L for C. albicans, has been reported overall to be as high as 3.5%.43–48”
Quote in the paperNot a substantial claim0 of 6 sources checked- cites [43] Pfaller, 2010, Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: a 10.5-year analysis of susceptibilities of Candida species to fluconazole and voriconazole as determined by CLSI standardized disk diffusion, J Clin Microbiol source
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- cites [44] Lyon, 2010, Antifungal susceptibility testing of Candida isolates from the Candida Surveillance Study, J Clin Microbiol source
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- cites [45] Pfaller, 2011, Candida bloodstream infections: comparison of species distributions and antifungal resistance patterns in community-onset and nosocomial isolates in the SENTRY Antimicrobial Surveillance Program, 2008-2009, Antimicrob Agents Chemother source
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- cites [46] Pfaller, 2012, Wild-type MIC distributions and epidemiological cutoff values for amphotericin B, flucytosine, and itraconazole and Candida spp. as determined by CLSI broth microdilution, J Clin Microbiol source
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- cites [47] Lockhart, 2012, Species identification and antifungal susceptibility testing of Candida bloodstream isolates from population-based surveillance studies in two U.S. cities from 2008 to 2011, J Clin Microbiol source
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- cites [48] Espinel-Ingroff, 2014, Multilaboratory study of epidemiological cutoff values for detection of resistance in eight Candida species to fluconazole, posaconazole, and voriconazole, Antimicrob Agents Chemother source
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- Premisecitation§ Introduction
A co-dominant mutation in the putative C-terminal activation domain confers hyperactivity of Tac1, leading to constitutive increased expression of CDR1 and CDR2.
“and that a co-dominant mutation in the putative C-terminal activation domain conferred hyperactivity of the Tac1 transcription factor, leading to constitutive increased expression of CDR1 and CDR2.80 , 81”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [80] Coste, 2004, TAC1, transcriptional activator of CDR genes, is a new transcription factor involved in the regulation of Candida albicans ABC transporters CDR1 and CDR2, Eukaryot Cell source
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- cites [81] Coste, 2006, A mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at chromosome 5 to mediate antifungal resistance in Candida albicans, Genetics source
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- Premisereasoning§ Introduction
Overexpression of azole-targeting efflux pumps is a key mechanism driving azole resistance in C. albicans.
“As such, the overexpression of azole-targeting efflux pumps is a key mechanism driving azole resistance in C. albicans.”
Quote in the paperSubstantial claim - Premisecitation§ Introduction
In C. albicans, the inability to demethylate lanosterol via Erg11 shunts sterol biosynthesis to alternative pathways, resulting in the accumulation of 14α-methylergosta-8,24(28)-dien-3β,6α-diol.
“In C. albicans, the inability to demethylate lanosterol via Erg11 shunts sterol biosynthesis production to other alternative biosynthesis pathways, resulting in the accumulation of 14α-methylergosta-8,24(28)-dien-3β,6α-diol.49”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [49] Watson, 1989, Defective sterol C5-6 desaturation and azole resistance: a new hypothesis for the mode of action of azole antifungals, Biochem Biophys Res Commun source
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- Premisenone given§ Introduction
Through inhibition of the ERG11-encoded protein 14α-lanosterol demethylase, the production of ergosterol normally required for membrane integrity is halted.
“Through inhibition of the ERG11-encoded protein 14α-lanosterol demethylase, the production of ergosterol normally required for membrane integrity is halted.”
Quote in the paperSubstantial claim - Premisenone given§ Introduction
C. albicans is able to utilize efflux systems to transport drugs extracellularly, thereby reducing intracellular drug concentrations.
“Like many infecting organisms, C. albicans is able to utilize efflux systems to transport drugs extracellularly, thereby reducing intracellular drug concentrations (Figure 1e).”
Quote in the paperSubstantial claim - Premisecitation§ Introduction
ZCF Tac1 regulates expression of both CDR1 and CDR2.
“Importantly, the zinc cluster transcription factor (ZCF) Tac1 was discovered to regulate the expression of both CDR1 and CDR2”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [80] Coste, 2004, TAC1, transcriptional activator of CDR genes, is a new transcription factor involved in the regulation of Candida albicans ABC transporters CDR1 and CDR2, Eukaryot Cell source
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- cites [81] Coste, 2006, A mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at chromosome 5 to mediate antifungal resistance in Candida albicans, Genetics source
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- Premisecitation§ Introduction
In two separate studies, isolates of C. albicans taken from HIV-infected individuals had increased mRNA levels of CDR1, which has been shown to confer resistance to the azole antifungals.
“In two separate studies, it was found that isolates of C. albicans taken from HIV-infected individuals had increased mRNA levels of CDR1, which has been shown to confer resistance to the azole antifungals.77–79”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [77] Sanglard, 1995, Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters, Antimicrob Agents Chemother source
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- cites [78] White, 1997, Increased mRNA levels of ERG16, CDR, and MDR1 correlate with increases in azole resistance in Candida albicans isolates from a patient infected with human immunodeficiency virus, Antimicrob Agents Chemother source
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- cites [79] Niimi, 2004, Regulated overexpression of CDR1 in Candida albicans confers multidrug resistance, J Antimicrob Chemother source
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- Premisecitation§ Introduction
Transcriptional profiling of three MDR1-overexpressing clinical isolates via DNA microarray analysis revealed 21 genes coordinately up-regulated with MDR1 and 7 genes down-regulated in all three isolates.
“Transcriptional profiling of three MDR1-overexpressing clinical isolates via DNA microarray analysis revealed 21 genes coordinately up-regulated with MDR1 and 7 genes down-regulated in all three isolates.103”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [103] Morschhauser, 2007, The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans, PLoS Pathog source
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- Premisecitation§ Introduction
Multiple gain-of-function mutations in Tac1 leading to increased expression of Cdr1 and Cdr2 efflux transporters have been described.
“Since then, multiple gain-of-function mutations in Tac1 (Figure 2a) leading to increased expression of the Cdr1 and Cdr2 efflux transporters have been described.81 , 85–87”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [81] Coste, 2006, A mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at chromosome 5 to mediate antifungal resistance in Candida albicans, Genetics source
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- cites [85] Siikala, 2010, Persistent Candida albicans colonization and molecular mechanisms of azole resistance in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) patients, J Antimicrob Chemother source
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- cites [86] Sasse, 2011, The transcription factor Ndt80 does not contribute to Mrr1-, Tac1-, and Upc2-mediated fluconazole resistance in Candida albicans, PLoS One source
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- cites [87] Coste, 2007, Genotypic evolution of azole resistance mechanisms in sequential Candida albicans isolates, Eukaryot Cell source
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- Premisecitation§ Introduction
Sequencing of the MRR1 alleles in the MDR1-overexpressing isolates F5 and G5 revealed a loss of heterozygosity and retention of two copies of a mutant MRR1 allele in both clinical isolates.
“Moreover, sequencing of the MRR1 alleles in the MDR1-overexpressing isolates F5 and G5 revealed a loss of heterozygosity and retention of two copies of a mutant MRR1 allele in both clinical isolates.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [103] Morschhauser, 2007, The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans, PLoS Pathog source
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- Premisecitation§ Introduction
Deletion of CDR1 in an azole-resistant clinical isolate containing a Tac1 gain-of-function mutation was directly responsible for reducing resistance to fluconazole, ketoconazole and itraconazole.
“It was further demonstrated that deletion of CDR1 in an azole-resistant clinical isolate containing a Tac1 gain-of-function mutation was directly responsible for reducing resistance to fluconazole, ketoconazole and itraconazole.84”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [84] Tsao, 2009, Relative contributions of the Candida albicans ABC transporters Cdr1p and Cdr2p to clinical azole resistance, Antimicrob Agents Chemother source
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- Premisecitation§ Introduction
Both constitutive and transient expression of CDR1 and CDR2 genes seem to be regulated via interactions at multiple cis-acting elements within the CDR1 and CDR2 promoters.
“Both the constitutive and transient expression of CDR1 and CDR2 genes seem to be regulated via interactions at multiple cis-acting elements within the CDR1 and CDR2 promoters.91”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [91] Prasad, 2015, The ABCs of Candida albicans multidrug transporter Cdr1, Eukaryot Cell source
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- Premisecitation§ Introduction
TAC1 gain-of-function mutant strains lacking either Med3 or Med15 have decreased fluconazole MICs.
“A study examining the co-activator requirements for hyperactive Tac1 regulation described decreased fluconazole MICs in TAC1 gain-of-function mutant strains lacking either Med3 or Med15, both of which are part of the mediator tail module.90”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [90] Liu, 2017, Mediator tail module is required for Tac1-activated CDR1 expression and azole resistance in Candida albicans, Antimicrob Agents Chemother source
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- Premisecitation§ Introduction
Fluconazole-susceptible and fluconazole-resistant matched pairs were shown to lack major polymorphic differences in the nucleotide sequence of their respective MDR1 promoter regions, despite high expression of MDR1 mRNA in the fluconazole-resistant isolate.
“Importantly, fluconazole-susceptible and fluconazole-resistant matched pairs (serial isolates taken from the same patient in which fluconazole resistance developed over time) were shown to lack major polymorphic differences in the nucleotide sequence of their respective MDR1 promoter regions, despite high expression of MDR1 mRNA in the fluconazole-resistant isolate.101”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [101] Wirsching, 2000, Activation of the multiple drug resistance gene MDR1 in fluconazole-resistant, clinical Candida albicans strains is caused by mutations in a trans-regulatory factor, J Bacteriol source
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- Premisecitation§ Introduction
Components of the tail module of the mediator complex are required for Tac1-activated CDR1 expression.
“More recently, components of the tail module of the mediator complex have been identified as required for Tac1-activated CDR1 expression.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [90] Liu, 2017, Mediator tail module is required for Tac1-activated CDR1 expression and azole resistance in Candida albicans, Antimicrob Agents Chemother source
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- Premisecitation§ Introduction
A link was established between the MDR1 gene and fluconazole resistance when serial isolates from HIV-infected patients with oropharyngeal candidiasis were analysed for ERG11 and MDR1 mRNA expression levels.
“It was not until serial isolates taken from HIV-infected patients with oropharyngeal candidiasis were analysed for ERG11 and MDR1 mRNA expression levels that a link was established between the MDR1 gene and fluconazole resistance.98”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [98] Franz, 1998, Multiple molecular mechanisms contribute to a stepwise development of fluconazole resistance in clinical Candida albicans strains, Antimicrob Agents Chemother source
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- Premisecitation§ Introduction
Deletion of MRR1 in each MDR1-overexpressing isolate did not yield identical MICs to strains lacking MDR1 in the same background.
“Interestingly, deletion of MRR1 in each MDR1-overexpressing isolate did not yield identical MICs to strains lacking MDR1 in the same background.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [103] Morschhauser, 2007, The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans, PLoS Pathog source
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- Premisecitation§ Introduction
Subsequent expression of GFP from the MDR1 promoter in the fluconazole-resistant isolate but not the fluconazole-susceptible isolate indicated that MDR1 expression was likely guided by a trans-regulatory factor.
“Subsequent expression of GFP from the MDR1 promoter in the fluconazole-resistant isolate but not the fluconazole-susceptible isolate indicated that MDR1 expression was likely guided by a trans-regulatory factor.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [101] Wirsching, 2000, Activation of the multiple drug resistance gene MDR1 in fluconazole-resistant, clinical Candida albicans strains is caused by mutations in a trans-regulatory factor, J Bacteriol source
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- Premisecitation§ Introduction
The zinc cluster transcription factor Mrr1 regulates the Mdr1 efflux pump.
“It was not until more recently that the zinc cluster transcription factor Mrr1 was discovered to regulate the Mdr1 efflux pump.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [103] Morschhauser, 2007, The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans, PLoS Pathog source
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- Premisecitation§ Introduction
Mutated MRR1 alleles were present in the MDR1-overexpressing clinical isolates.
“Similar to the zinc cluster transcription factor-encoding gene TAC1 in CDR1- and CDR2-overexpressing isolates, mutated MRR1 alleles were present in the MDR1-overexpressing clinical isolates.103”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [103] Morschhauser, 2007, The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans, PLoS Pathog source
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- Premisecitation§ Introduction
Overexpression of ERG11 contributes to decreased azole susceptibility through increased production of the azole target 14α-lanosterol demethylase.
“The overexpression of ERG11 had been shown to contribute to decreased azole susceptibility through increased production of the azole target 14α-lanosterol demethylase (Figure 1a).78 , 98 , 106 , 107”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [78] White, 1997, Increased mRNA levels of ERG16, CDR, and MDR1 correlate with increases in azole resistance in Candida albicans isolates from a patient infected with human immunodeficiency virus, Antimicrob Agents Chemother source
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- cites [98] Franz, 1998, Multiple molecular mechanisms contribute to a stepwise development of fluconazole resistance in clinical Candida albicans strains, Antimicrob Agents Chemother source
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- cites [106] Perea, 2001, Prevalence of molecular mechanisms of resistance to azole antifungal agents in Candida albicans strains displaying high-level fluconazole resistance isolated from human immunodeficiency virus-infected patients, Antimicrob Agents Chemother source
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- cites [107] MacPherson, 2005, Candida albicans zinc cluster protein Upc2p confers resistance to antifungal drugs and is an activator of ergosterol biosynthetic genes, Antimicrob Agents Chemother source
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- Premisecitation§ Introduction
Upc2 has a regulatory role in more than just sterol biosynthesis genes.
“Upc2, however, was also shown to have a regulatory role in more than just sterol biosynthesis genes.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [109] Dunkel, 2008, A gain-of-function mutation in the transcription factor Upc2p causes upregulation of ergosterol biosynthesis genes and increased fluconazole resistance in a clinical Candida albicans isolate, Eukaryot Cell source
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- cites [110] Znaidi, 2008, Genomewide location analysis of Candida albicans Upc2p, a regulator of sterol metabolism and azole drug resistance, Eukaryot Cell source
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- cites [111] Schubert, 2011, Regulation of efflux pump expression and drug resistance by the transcription factors Mrr1, Upc2, and Cap1 in Candida albicans, Antimicrob Agents Chemother source
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- Premisecitation§ Introduction
Gain-of-function mutations in Upc2 lead to increased gene expression of ERG11 conferring fluconazole resistance in clinical isolates.
“As with the zinc cluster transcription factors Tac1 and Mrr1, gain-of-function mutations in Upc2 were found to lead to increased gene expression of ERG11 conferring fluconazole resistance in clinical isolates (Figure 2c).109 , 112–114”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [109] Dunkel, 2008, A gain-of-function mutation in the transcription factor Upc2p causes upregulation of ergosterol biosynthesis genes and increased fluconazole resistance in a clinical Candida albicans isolate, Eukaryot Cell source
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- cites [112] Heilmann, 2010, An A643T mutation in the transcription factor Upc2p causes constitutive ERG11 upregulation and increased fluconazole resistance in Candida albicans, Antimicrob Agents Chemother source
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- cites [113] Hoot, 2011, An A643V amino acid substitution in Upc2p contributes to azole resistance in well-characterized clinical isolates of Candida albicans, Antimicrob Agents Chemother source
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- cites [114] Flowers, 2012, Gain-of-function mutations in UPC2 are a frequent cause of ERG11 upregulation in azole-resistant clinical isolates of Candida albicans, Eukaryot Cell source
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- Premisecitation§ Introduction
ChIP-microarray location analysis identified 202 promoters bound by Upc2, including not only ergosterol biosynthesis genes (NCP1, ERG11, ERG1, ERG2, ERG24, ERG4, ERG5, ERG6, ERG9, ERG10, ERG25, ERG251 and UPC2) but also other transcription factors and the drug transporter genes CDR1 and MDR1.
“and ChIP-microarray location analysis identified 202 promoters bound by Upc2, including not only ergosterol biosynthesis genes (NCP1, ERG11, ERG1, ERG2, ERG24, ERG4, ERG5, ERG6, ERG9, ERG10, ERG25, ERG251 and UPC2) but also other transcription factors and the drug transporter genes CDR1 and MDR1.109–111”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [109] Dunkel, 2008, A gain-of-function mutation in the transcription factor Upc2p causes upregulation of ergosterol biosynthesis genes and increased fluconazole resistance in a clinical Candida albicans isolate, Eukaryot Cell source
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- cites [110] Znaidi, 2008, Genomewide location analysis of Candida albicans Upc2p, a regulator of sterol metabolism and azole drug resistance, Eukaryot Cell source
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- cites [111] Schubert, 2011, Regulation of efflux pump expression and drug resistance by the transcription factors Mrr1, Upc2, and Cap1 in Candida albicans, Antimicrob Agents Chemother source
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- Premisecitation§ Introduction
Through genome-wide gene expression profiling, several ergosterol biosynthesis genes, including ERG11, were determined to be coordinately up-regulated with UPC2 in fluconazole-resistant isolates.
“Through genome-wide gene expression profiling, several ergosterol biosynthesis genes, including ERG11, were determined to be coordinately up-regulated with UPC2 in fluconazole-resistant isolates”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [109] Dunkel, 2008, A gain-of-function mutation in the transcription factor Upc2p causes upregulation of ergosterol biosynthesis genes and increased fluconazole resistance in a clinical Candida albicans isolate, Eukaryot Cell source
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- cites [110] Znaidi, 2008, Genomewide location analysis of Candida albicans Upc2p, a regulator of sterol metabolism and azole drug resistance, Eukaryot Cell source
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- cites [111] Schubert, 2011, Regulation of efflux pump expression and drug resistance by the transcription factors Mrr1, Upc2, and Cap1 in Candida albicans, Antimicrob Agents Chemother source
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- Premisecitation§ Introduction
Overexpression of Upc2 via expression of the ORF from the MET3 promoter increased resistance to fluconazole and ketoconazole.
“Importantly, overexpression of Upc2 via expression of the ORF from the MET3 promoter increased resistance to fluconazole and ketoconazole”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [107] MacPherson, 2005, Candida albicans zinc cluster protein Upc2p confers resistance to antifungal drugs and is an activator of ergosterol biosynthetic genes, Antimicrob Agents Chemother source
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- Premisecitation§ Introduction
UPC2 in C. albicans up-regulates ergosterol biosynthesis genes ERG2 and ERG11 when exposed to fluconazole.
“Initially identified as a homologue of the S. cerevisiae (ScUPC2) gene, UPC2 in C. albicans was initially reported to up-regulate the ergosterol biosynthesis genes ERG2 and ERG11 when exposed to fluconazole.105”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [105] Silver, 2004, Role of Candida albicans transcription factor Upc2p in drug resistance and sterol metabolism, Eukaryot Cell source
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- Premisecitation§ Introduction
In 2015, the first clinical isolate containing putative gain-of-function mutations in the ZCF Mrr2 was described, possessing amino acid substitutions that appeared to increase CDR1 but not CDR2 expression.
“In 2015, the first clinical isolate containing putative gain-of-function mutations in the ZCF Mrr2 was described, possessing amino acid substitutions that appeared to increase CDR1 but not CDR2 expression.117”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [117] Li, 2015, Trisomy of chromosome R confers resistance to triazoles in Candida albicans, Med Mycol source
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- Premisenone given§ Introduction
Most ERG11 mutations are thought to alter the ability of the azoles to bind and inhibit the lanosterol demethylase enzyme, either through steric hindrance in the ligand-binding pocket where the azole antifungals compete with the ergosterol precursor or by altering or reducing important interactions, such as the H-bond interactions with the azole ring and the haem group of the Erg11 protein.
“Most ERG11 mutations are thought to alter the ability of the azoles to bind and inhibit the lanosterol demethylase enzyme, either through steric hindrance in the ligand-binding pocket where the azole antifungals compete with the ergosterol precursor or by altering or reducing important interactions, such as the H-bond interactions with the azole ring and the haem group of the Erg11 protein.”
Quote in the paperNot a substantial claim - Premisecitation§ Introduction
This altered susceptibility to the azoles was noted to likely be a result of altered interaction with azole binding and overall reduced fluconazole-binding affinity to the mutant 14α-lanosterol demethylase target enzyme.
“This altered susceptibility to the azoles was noted to likely be a result of altered interaction with azole binding and overall reduced fluconazole-binding affinity to the mutant 14α-lanosterol demethylase target enzyme.122 , 123”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [122] Kelly, 1999, Y132H substitution in Candida albicans sterol 14α-demethylase confers fluconazole resistance by preventing binding to haem, FEMS Microbiol Lett
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- cites [123] Kelly, 1999, The G464S amino acid substitution in Candida albicans sterol 14α-demethylase causes fluconazole resistance in the clinic through reduced affinity, Biochem Biophys Res Commun source
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- Premisecitation§ Introduction
Multiple amino acid substitutions in Mrr1 originating from both human clinical isolates and in vitro-generated strains are gain-of-function mutations driving constitutive MDR1 expression.
“Indeed, multiple amino acid substitutions in Mrr1 originating from both human clinical isolates and in vitro-generated strains have been shown to be gain-of-function mutations driving constitutive MDR1 expression (Figure 2b).104”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [104] Dunkel, 2008, Mutations in the multi-drug resistance regulator MRR1, followed by loss of heterozygosity, are the main cause of MDR1 overexpression in fluconazole-resistant Candida albicans strains, Mol Microbiol source
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- Premisecitation§ Introduction
14α-Methylergosta-8,24(28)-dien-3β,6α-diol accumulates in C. albicans cells following treatment with fluconazole.
“14α-Methylergosta-8,24(28)-dien-3β,6α-diol, a metabolic by-product not normally produced in significant amounts during normal ergosterol biosynthesis, was found to accumulate in C. albicans cells following treatment with fluconazole.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [50] Kelly, 1997, Resistance to fluconazole and cross-resistance to amphotericin B in Candida albicans from AIDS patients caused by defective sterol Δ5,6-desaturation, FEBS Letters source
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- Premisecitation§ Introduction
For both TAC1 and MRR1, loss of heterozygosity was responsible in some clinical isolates for homozygous gain-of-function mutations conferring increased efflux pump expression and azole resistance.
“it has been shown for both TAC1 and MRR1 that loss of heterozygosity was responsible in some clinical isolates for homozygous gain-of-function mutations conferring increased efflux pump expression and azole resistance.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [81] Coste, 2006, A mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at chromosome 5 to mediate antifungal resistance in Candida albicans, Genetics source
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- cites [104] Dunkel, 2008, Mutations in the multi-drug resistance regulator MRR1, followed by loss of heterozygosity, are the main cause of MDR1 overexpression in fluconazole-resistant Candida albicans strains, Mol Microbiol source
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- Interpretationcitation§ Introduction
Loss of heterozygosity at gene loci in isolates serially passaged in azole-containing media and in laboratory strains passaged through mice models suggests significant genetic rearrangements take place as a result of host and drug stress.
“Loss of heterozygosity at gene loci of isolates serially passaged in azole-containing media, as well as laboratory strains passaged through mice models of haematogenously disseminated disease, both suggest that significant genetic rearrangements take place as a result of host and drug stress.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [152] Cowen, 2000, Evolution of drug resistance in experimental populations of Candida albicans, J Bacteriol source
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- cites [153] Forche, 2005, Demonstration of loss of heterozygosity by single-nucleotide polymorphism microarray analysis and alterations in strain morphology in Candida albicans strains during infection, Eukaryot Cell source
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- Premisecitation§ Introduction
Studies using comparative genome hybridization observed aneuploidies mainly on chromosomes 1, 2, and 5 in various C. albicans laboratory strains.
“Studies using comparative genome hybridization in various C. albicans laboratory strains observed aneuploidies mainly on chromosomes 1, 2 and 5”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [154] Selmecki, 2005, Comparative genome hybridization reveals widespread aneuploidy in Candida albicans laboratory strains, Mol Microbiol source
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- cites [155] Selmecki, 2006, Aneuploidy and isochromosome formation in drug-resistant Candida albicans, Science source
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- Interpretationcitation§ Introduction
Other Erg11 substitutions not predicted to directly interact with azole binding, such as G450E on the fungal CYP51-specific β5-hairpin, may indirectly affect resistance through interaction with cytochrome P450 reductase-Erg11 interactions.
“other substitutions that are not predicted to directly interact with azole binding, such as the G450E substitution found on the fungal CYP51-specific β5-hairpin, may indirectly affect resistance through interaction with cytochrome P450 reductase–Erg11 interactions.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [139] Hargrove, 2017, Structural analyses of Candida albicans sterol 14α-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis, J Biol Chem source
Not checked in the free run.
- Premisecitation§ Introduction
Several mutant ERG3 clinical isolates have been identified and reportedly possess resistance to azole antifungals and cross-resistance to amphotericin B.
“several mutant ERG3 clinical isolates have been identified and reportedly possess resistance to the azole antifungals and cross-resistance to the polyene amphotericin B.”
Quote in the paperNot a substantial claim0 of 6 sources checked- cites [50] Kelly, 1997, Resistance to fluconazole and cross-resistance to amphotericin B in Candida albicans from AIDS patients caused by defective sterol Δ5,6-desaturation, FEBS Letters source
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- cites [129] Martel, 2010, A clinical isolate of Candida albicans with mutations in ERG11 (encoding sterol 14α-demethylase) and ERG5 (encoding C22 desaturase) is cross resistant to azoles and amphotericin B, Antimicrob Agents Chemother source
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- cites [142] Martel, 2010, Identification and characterization of four azole-resistant erg3 mutants of Candida albicans, Antimicrob Agents Chemother source
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- cites [143] Miyazaki, 1999, Cloning, sequencing, expression and allelic sequence diversity of ERG3 (C-5 sterol desaturase gene) in Candida albicans, Gene source
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- cites [144] Howell, 1990, A comparison of the sterol content of multiple isolates of the Candida albicans Darlington strain with other clinically azole-sensitive and -resistant strains, J Appl Bacteriol source
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- cites [145] Morio, 2012, Amino acid substitutions in the Candida albicans sterol Δ5,6-desaturase (Erg3p) confer azole resistance: characterization of two novel mutants with impaired virulence, J Antimicrob Chemother source
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- Premisecitation§ Introduction
Some genomic changes such as isochromosome formation confer azole resistance in C. albicans.
“it was later shown that some genomic changes such as isochromosome formation confer azole resistance in C. albicans.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [154] Selmecki, 2005, Comparative genome hybridization reveals widespread aneuploidy in Candida albicans laboratory strains, Mol Microbiol source
Not checked in the free run.
- cites [155] Selmecki, 2006, Aneuploidy and isochromosome formation in drug-resistant Candida albicans, Science source
Not checked in the free run.
- Premisecitation§ Introduction
Some Erg11 substitutions show relatively loose azole binding but significant contribution to azole resistance in in vitro C. albicans susceptibility testing.
“Despite some substitutions showing relatively loose azole binding, their observed contribution to azole resistance in in vitro C. albicans susceptibility testing was significant”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [141] Warrilow, 2019, The evolution of azole resistance in Candida albicans sterol 14α-demethylase (CYP51) through incremental amino acid substitutions, Antimicrob Agents Chemother source
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- Premisecitation§ Introduction
Erg11 variants differ substantially in their baseline catalytic turnover and affinity for azole binding.
“Erg11 variants differ substantially in their baseline catalytic turnover and affinity for azole binding.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [141] Warrilow, 2019, The evolution of azole resistance in Candida albicans sterol 14α-demethylase (CYP51) through incremental amino acid substitutions, Antimicrob Agents Chemother source
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- Premisenone given§ Introduction
Alterations in sterol biosynthesis pathways in C. albicans are an important but rare clinical mechanism of azole antifungal resistance.
“Alterations in sterol biosynthesis pathways in C. albicans remain an important, albeit rare, clinical mechanism of azole antifungal resistance”
Quote in the paperNot a substantial claim - Premisecitation§ Introduction
Isolates with defective C-5 sterol desaturase avoid accumulation of 14α-methylergosta-8,24(28)-dien-3β,6α-diol after treatment with fluconazole.
“isolates with defective C-5 sterol desaturase, which lacked detectable amounts of ergosterol presumably because they no longer possessed the Erg3 enzyme function required for ergosterol production, avoided accumulation of 14α-methylergosta-8,24(28)-dien-3β,6α-diol after treatment with fluconazole.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [50] Kelly, 1997, Resistance to fluconazole and cross-resistance to amphotericin B in Candida albicans from AIDS patients caused by defective sterol Δ5,6-desaturation, FEBS Letters source
Not checked in the free run.
- Premisecitation§ Introduction
The crystal structure of C. albicans Erg11 has been resolved.
“the crystal structure of the Erg11 protein of C. albicans has been resolved”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [139] Hargrove, 2017, Structural analyses of Candida albicans sterol 14α-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis, J Biol Chem source
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- cites [140] Keniya, 2018, Crystal structures of full-length lanosterol 14α-demethylases of prominent fungal pathogens Candida albicans and Candida glabrata provide tools for antifungal discovery, Antimicrob Agents Chemother source
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- Premisecitation§ Introduction
Single Erg11 substitutions show variable responses to fluconazole and other triazoles, ranging from no effect to a 16-fold increase in MIC over the fluconazole-susceptible parent.
“Single substitutions in Erg11 showed variable responses to fluconazole and other triazoles ranging from no effect to a 16-fold increase in MIC over the fluconazole-susceptible parent”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [138] Flowers, 2015, Contribution of clinically derived mutations in ERG11 to azole resistance in Candida albicans, Antimicrob Agents Chemother source
Not checked in the free run.
- Premisecitation§ Introduction
Double Erg11 substitutions increase MIC beyond the individual contribution to azole resistance of any single amino acid substitution.
“double substitutions in Erg11 further increased the MIC beyond the individual contribution to azole resistance of any single amino acid substitution.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [138] Flowers, 2015, Contribution of clinically derived mutations in ERG11 to azole resistance in Candida albicans, Antimicrob Agents Chemother source
Not checked in the free run.
- Premisecitation§ Introduction
Changes within the ERG3 promoter that affect expression and activity may be sufficient to confer azole resistance in niche-specific instances without affecting C. albicans pathogenicity.
“changes within the ERG3 promoter that affect expression and activity may be sufficient to confer azole resistance in niche-specific instances without affecting C. albicans pathogenicity”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [149] Luna-Tapia, 2018, Loss of Upc2p-inducible ERG3 transcription is sufficient to confer niche-specific azole resistance without compromising Candida albicans pathogenicity, MBio source
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- Interpretationcitation§ Introduction
Changes in the ERG3 locus are potentially more clinically relevant than previously believed.
“which implicates changes in the ERG3 locus as potentially more clinically relevant than previously believed.”
Quote in the paperSubstantial claim - Interpretationcitation§ Introduction
Some Erg11 substitutions (Y132F/H, K143R, G307S, S405F) are located on the exposed active-site cavity of Erg11 and presumably directly influence or interfere with azole binding.
“some substitutions, such as Y132F/H, K143R, G307S and S405F, are located on the exposed active-site cavity of the Erg11 protein and presumably directly influence or interfere with azole binding”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [139] Hargrove, 2017, Structural analyses of Candida albicans sterol 14α-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis, J Biol Chem source
Not checked in the free run.
- Interpretationreasoning§ Introduction
Mutations and amino acid substitutions that confer defects in Erg3 confer resistance to azole antifungals due to the inability to produce 14α-methylergosta-8,24(28)-dien-3β,6α-diol.
“mutations and amino acid substitutions that confer defects in Erg3 also confer resistance to the azole antifungals, specifically due to the inability to produce 14α-methylergosta-8,24(28)-dien-3β,6α-diol, which requires Erg3.”
Quote in the paperSubstantial claim - Premisecitation§ Introduction
Hsp90 is involved in azole tolerance as part of the Rim pathway in C. albicans.
“Hsp90 is also involved in azole tolerance as part of the Rim pathway in C. albicans.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [169] Garnaud, 2018, The Rim pathway mediates antifungal tolerance in Candida albicans through newly identified Rim101 transcriptional targets, including Hsp90 and Ipt1, Antimicrob Agents Chemother source
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- Premisecitation§ Introduction
Fluconazole import displays saturation kinetics in de-energized Candida cells unable to efflux drug via active transport mechanisms like the ABC transporter Cdr1.
“fluconazole import displayed saturation kinetics in de-energized cells unable to efflux drug via active transport mechanisms like the ABC transporter Cdr1.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [160] Mansfield, 2010, Azole drugs are imported by facilitated diffusion in Candida albicans and other pathogenic fungi, PLoS Pathog source
Not checked in the free run.
- Premisenone given§ Introduction
Hsp90 is not directly involved in azole resistance.
“While not directly involved in azole resistance, Hsp90 is an important molecular chaperone”
Quote in the paperNot a substantial claim - Premisereasoning§ Introduction
Biofilms are intrinsically resistant to antifungal drugs, particularly azoles, leading to therapeutic failure.
“Biofilms are intrinsically resistant to antifungal drugs, in particular the azoles, leading to therapeutic failure.”
Quote in the paperNot a substantial claim - Premisecitation§ Introduction
In serial clinical C. albicans isolates from a patient treated with fluconazole over 2 years, azole resistance was initially dependent on Hsp90 and calcineurin, but evolved towards Hsp90-independent mechanisms over time.
“serial clinical isolates taken from the same patient treated with fluconazole over 2 years showed that azole resistance was initially dependent on Hsp90 and its client protein calcineurin, though resistance evolved towards Hsp90-independent resistance mechanisms over time.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [164] Cowen, 2005, Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi, Science source
Not checked in the free run.
- Premisecitation§ Introduction
Hsp90 potentiates the evolution of drug resistance traits, including some azole resistance mechanisms.
“has been shown to potentiate the evolution of drug resistance traits, including some azole resistance mechanisms.”
Quote in the paperNot a substantial claim0 of 6 sources checked- cites [162] Cowen, 2008, The evolution of fungal drug resistance: modulating the trajectory from genotype to phenotype, Nat Rev Microbiol source
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- cites [163] Cowen, 2006, Genetic architecture of Hsp90-dependent drug resistance, Eukaryot Cell source
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- cites [164] Cowen, 2005, Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi, Science source
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- cites [165] Singh, 2009, Hsp90 governs echinocandin resistance in the pathogenic yeast Candida albicans via calcineurin, PLoS Pathog source
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- cites [166] LaFayette, 2010, PKC signaling regulates drug resistance of the fungal pathogen Candida albicans via circuitry comprised of Mkc1, calcineurin, and Hsp90, PLoS Pathog source
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- cites [167] Cowen, 2009, Hsp90 orchestrates stress response signaling governing fungal drug resistance, PLoS Pathog source
Not checked in the free run.
- Premisecitation§ Introduction
There is increasing evidence of Hsp90's regulatory role in azole resistance development.
“there is increasing evidence of its regulatory role in azole resistance development.”
Quote in the paperNot a substantial claim0 of 6 sources checked- cites [162] Cowen, 2008, The evolution of fungal drug resistance: modulating the trajectory from genotype to phenotype, Nat Rev Microbiol source
Not checked in the free run.
- cites [163] Cowen, 2006, Genetic architecture of Hsp90-dependent drug resistance, Eukaryot Cell source
Not checked in the free run.
- cites [164] Cowen, 2005, Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi, Science source
Not checked in the free run.
- cites [165] Singh, 2009, Hsp90 governs echinocandin resistance in the pathogenic yeast Candida albicans via calcineurin, PLoS Pathog source
Not checked in the free run.
- cites [166] LaFayette, 2010, PKC signaling regulates drug resistance of the fungal pathogen Candida albicans via circuitry comprised of Mkc1, calcineurin, and Hsp90, PLoS Pathog source
Not checked in the free run.
- cites [167] Cowen, 2009, Hsp90 orchestrates stress response signaling governing fungal drug resistance, PLoS Pathog source
Not checked in the free run.
- Premisecitation§ Introduction
Hsp90, by stabilizing calcineurin and the pathway essential in cellular drug-induced stress response, affects azole resistance and resistance to echinocandins.
“by stabilizing the calcineurin protein and the pathway that is essential in the cellular drug-induced stress response, Hsp90 has been shown to affect not only azole resistance but resistance to the echinocandin drug class as well.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [165] Singh, 2009, Hsp90 governs echinocandin resistance in the pathogenic yeast Candida albicans via calcineurin, PLoS Pathog source
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- cites [167] Cowen, 2009, Hsp90 orchestrates stress response signaling governing fungal drug resistance, PLoS Pathog source
Not checked in the free run.
- cites [168] Sanglard, 2003, Calcineurin A of Candida albicans: involvement in antifungal tolerance, cell morphogenesis and virulence, Mol Microbiol source
Not checked in the free run.
- Interpretationcitation§ Introduction
Aneuploidy plays an important role in adaptive fitness to selective pressures under these circumstances.
“suggests that aneuploidy plays an important role in adaptive fitness to selective pressures under these circumstances.”
Quote in the paperSubstantial claim - Interpretationcitation§ Introduction
Aneuploidy is important in the microevolution of drug-resistant C. albicans.
“underscores the importance of aneuploidy in the microevolution of drug-resistant C. albicans.”
Quote in the paperSubstantial claim - Premisecitation§ Introduction
Tetraploid C. albicans cells can generate diverse fitness and heterogeneity through increased rates of heterozygosity loss.
“The discovery of tetraploid cells of C. albicans, containing four homologous sets of chromosomes, and their ability to generate a diverse range of fitness and heterogeneity through increased rates of heterozygosity loss”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [157] Legrand, 2004, Homozygosity at the MTL locus in clinical strains of Candida albicans: karyotypic rearrangements and tetraploid formation, Mol Microbiol source
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- cites [158] Hickman, 2015, Parasexual ploidy reduction drives population heterogeneity through random and transient aneuploidy in Candida albicans, Genetics source
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- Premisenone given§ Introduction
The carrier protein(s) responsible for importing fluconazole and presumably other azoles have not yet been identified.
“The carrier protein(s) responsible for importing fluconazole and presumably the other azoles, however, has/have not yet been identified despite prolific research.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ Introduction
Fluconazole is taken up by a carrier protein via facilitated diffusion.
“The kinetics of fluconazole import, therefore, suggest that fluconazole is taken up by means of a carrier protein via facilitated diffusion”
Quote in the paperNot a substantial claim - Interpretationnone given§ Introduction
C. albicans has multiple defence mechanisms used alone and in combination to overcome azole inhibition.
“C. albicans has an arsenal of defence mechanisms that it uses, alone and in combination, to overcome inhibition by the azole antifungals.”
Quote in the paperSubstantial claim - Premisecitation§ Introduction
Clinical isolates from patients with persistent candidaemia have significantly higher FoG and SMG levels than isolates from patients whose candidaemia cleared after a single fluconazole course.
“significantly higher FoG and SMG levels were observed in clinical isolates originating in patients with persistent candidaemia.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [194] Rosenberg, 2018, Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia, Nat Commun source
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- Premisecitation§ Introduction
Tolerant C. albicans cells do not have reduced growth rates, in contrast to tolerance in bacteria.
“in contrast to tolerance in bacteria, tolerant C. albicans cells did not have reduced growth rates.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [194] Rosenberg, 2018, Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia, Nat Commun source
Not checked in the free run.
- Premisecitation§ Introduction
Tested isolates in both groups had in vitro MICs indicating fluconazole susceptibility.
“the tested isolates in both groups all had in vitro MICs considered to indicate fluconazole susceptibility”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [194] Rosenberg, 2018, Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia, Nat Commun source
Not checked in the free run.
- Interpretationreasoning§ Introduction
C. albicans isolates with high FoG or SMG have a larger subpopulation that can respond to high antifungal drug stress better than isolates with low FoG or SMG.
“C. albicans isolates with high levels of FoG or SMG suggest a larger subpopulation that can respond to high levels of antifungal drug stress better than isolates with low FoG or SMG.”
Quote in the paperSubstantial claim - Premisecitation§ Introduction
RTA3 is associated with increased azole tolerance and trailing growth in C. albicans.
“RTA3, encoding a putative lipid translocase coordinately up-regulated with CDR1 in clinical isolates with Tac1 gain-of-function mutations, has been associated with increased azole tolerance and trailing growth in C. albicans.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [188] Whaley, 2016, The RTA3 gene, encoding a putative lipid translocase, influences the susceptibility of Candida albicans to fluconazole, Antimicrob Agents Chemother source
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- Premisecitation§ Introduction
Several adjuvant drugs can reduce FoG but not MIC in clinical isolates.
“the identification of several adjuvant drugs that could reduce FoG but not MIC in clinical isolates”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [194] Rosenberg, 2018, Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia, Nat Commun source
Not checked in the free run.
- Interpretationreasoning§ Introduction
Drug tolerance in C. albicans may be an overlooked issue of significant clinical relevance.
“suggests that drug tolerance in C. albicans may be an overlooked issue of significant clinical relevance.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Introduction
Up-regulation of efflux pumps results in biofilm recalcitrance to treatment with antifungal agents.
“This up-regulation of efflux pumps results in biofilm recalcitrance to treatment with antifungal agents.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ Introduction
β-1,3-glucan and its delivery/accumulation pathway contribute to drug resistance properties of biofilms.
“The polysaccharide β-1,3-glucan and the pathway involved in its delivery and accumulation in the biofilm matrix is therefore believed to be contributing to drug resistance properties of the biofilms.”
Quote in the paperNot a substantial claim - Interpretationcitation§ Introduction
FoG and SMG are potential parameters to guide treatment outcome in patients with candidaemia.
“identified FoG and SMG as potential parameters to guide treatment outcome in patients with candidaemia.”
Quote in the paperSubstantial claim - Premisecitation§ Introduction
Transposon-based mutagenesis and disruption of C. albicans genome in a haploid strain identified potential genes involved in drug stress response.
“transposon-based mutagenesis and disruption of the C. albicans genome in a haploid strain identified a number of potential genes involved in drug stress response through Gene Set Enrichment Analysis”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [195] Gao, 2018, Candida albicans gains azole resistance by altering sphingolipid composition, Nat Commun source
Not checked in the free run.
- Premisecitation§ Introduction
Biofilm matrix glucan binds and sequesters antifungal drugs, including fluconazole, preventing intracellular action.
“the biofilm matrix glucan has demonstrated the ability to bind and sequester antifungal drugs, including fluconazole, preventing them from acting intracellularly.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [179] Taff, 2012, A Candida biofilm-induced pathway for matrix glucan delivery: implications for drug resistance, PLoS Pathog source
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- Classified as probably not a substantial claim. 67
- May combine two claims. 64
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ AbstractInfections with C. albicans range from superficial mucosal and dermatological infections to life-threatening infections of the bloodstream and vital organs.
“Infections with C. albicans can range from superficial mucosal and dermatological infections to life-threatening infections of the bloodstream and vital organs.”
Quote in the paperNot a substantial claim0 of 7 sources checked- cites [1] Hoffmann, 2013, Archaea and fungi of the human gut microbiome: correlations with diet and bacterial residents, PLoS One source
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- cites [2] Ghannoum, 2010, Characterization of the oral fungal microbiome (mycobiome) in healthy individuals, PLoS Pathog source
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- cites [3] Findley, 2013, Topographic diversity of fungal and bacterial communities in human skin, Nature source
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- cites [4] Merenstein, 2013, Colonization by Candida species of the oral and vaginal mucosa in HIV-infected and noninfected women, AIDS Res Hum Retroviruses source
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- cites [5] Arendrup, 2017, Multidrug-resistant Candida: epidemiology, molecular mechanisms, and treatment, J Infect Dis source
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- cites [6] Koehler, 2019, Morbidity and mortality of candidaemia in Europe: an epidemiologic meta-analysis, Clin Microbiol Infect source
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- cites [7] Chowdhary, 2016, Multidrug-resistant Candida auris: ‘new kid on the block’ in hospital-associated infections?, J Hosp Infect source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ AbstractCandida albicans is an opportunistic yeast and the major human fungal pathogen in the USA and many other regions of the world.
“Candida albicans is an opportunistic yeast and the major human fungal pathogen in the USA, as well as in many other regions of the world.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Whaley, 2016, Azole antifungal resistance in Candida albicans and emerging non-albicans Candida species, Front Microbiol
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionFluconazole is often either the drug of choice or recommended alternative to the echinocandin class for the treatment of most invasive Candida infections.
“Fluconazole is often either the drug of choice or recommended alternative to the echinocandin class for the treatment of most invasive Candida infections.30”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Pappas, 2016, Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America, Clin Infect Dis source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionOf all Candida species, C. albicans dominates almost all patient groups and disease manifestations in terms of incidence, followed by C. glabrata, C. parapsilosis, C. tropicalis and C. krusei.
“Of all Candida species, Candida albicans dominates almost all patient groups and disease manifestations in terms of incidence, followed by Candida glabrata, Candida parapsilosis, Candida tropicalis and Candida krusei.16”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Whaley, 2016, Azole antifungal resistance in Candida albicans and emerging non-albicans Candida species, Front Microbiol
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ IntroductionC. parapsilosis is usually susceptible to azoles but recent reports suggest the emergence of resistance in invasive infections.
“Similarly, C. parapsilosis is usually susceptible to azoles but recent reports suggest the emergence of resistance in invasive infections.33–36”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [33] Moudgal, 2005, Multiechinocandin- and multiazole-resistant Candida parapsilosis isolates serially obtained during therapy for prosthetic valve endocarditis, Antimicrob Agents Chemother source
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- cites [34] Sarvikivi, 2005, Emergence of fluconazole resistance in a Candida parapsilosis strain that caused infections in a neonatal intensive care unit, J Clin Microbiol source
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- cites [35] Canton, 2011, Prospective multicenter study of the epidemiology, molecular identification, and antifungal susceptibility of Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis isolated from patients with candidemia, Antimicrob Agents Chemother source
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- cites [36] Pfaller, 2014, Regional data analysis of Candida non-albicans strains collected in United States medical sites over a 6-year period, 2006-2011, Mycoses source
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Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionCandida lusitaniae is resistant, either intrinsically or acquired, to amphotericin B.
“Candida lusitaniae, on the other hand, is resistant, either intrinsically or acquired, to amphotericin B”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [17] Castanheira, 2016, Antifungal susceptibility patterns of a global collection of fungal isolates: results of the SENTRY Antifungal Surveillance Program (2013), Diagn Microbiol Infect Dis source
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- cites [27] Chowdhary, 2017, Candida auris: a rapidly emerging cause of hospital-acquired multidrug-resistant fungal infections globally, PLoS Pathog source
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- cites [36] Pfaller, 2014, Regional data analysis of Candida non-albicans strains collected in United States medical sites over a 6-year period, 2006-2011, Mycoses source
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- cites [37] Khan, 2019, Candida lusitaniae in Kuwait: prevalence, antifungal susceptibility and role in neonatal fungemia, PLoS One source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ IntroductionC. albicans is a member of native human microbiota and colonizes the gastrointestinal tract, reproductive tract, oral cavity and skin of most humans.
“C. albicans is a member of native human microbiota and, as a commensal organism, colonizes the gastrointestinal (GI) tract, reproductive tract, oral cavity and skin of most humans.28”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28] Nobile, 2015, Candida albicans biofilms and human disease, Annu Rev Microbiol source
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Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionC. glabrata is the second most common species in the USA and North-Western Europe in the non-outbreak setting.
“C. glabrata is the second most common species in the USA and North-Western Europe in the non-outbreak setting.17 , 18”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [17] Castanheira, 2016, Antifungal susceptibility patterns of a global collection of fungal isolates: results of the SENTRY Antifungal Surveillance Program (2013), Diagn Microbiol Infect Dis source
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- cites [18] Goncalves, 2016, Vulvovaginal candidiasis: epidemiology, microbiology and risk factors, Crit Rev Microbiol source
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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationreasoning§ IntroductionFailure to identify a possible environmental reservoir for C. albicans suggests that this species is exquisitely adapted to healthy mammalian hosts.
“Failure to identify a possible environmental reservoir for C. albicans suggests that this species is exquisitely adapted to healthy mammalian hosts.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Premisecitation§ AbstractThe azole antifungals remain an important mainstay treatment of candidiasis.
“The azole antifungals remain an important mainstay treatment of candidiasis”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [30] Pappas, 2016, Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America, Clin Infect Dis source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ IntroductionAlthough varying rates of fluconazole resistance have been observed for C. albicans in particular types of infection, resistance rates remain low in general.
“Although varying rates of fluconazole resistance have been observed for C. albicans in particular types of infection, resistance rates remain low in general.9 , 31 , 32”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [9] Diekema, 2012, The changing epidemiology of healthcare-associated candidemia over three decades, Diagn Microbiol Infect Dis source
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- cites [31] Pfaller, 2015, Isavuconazole, micafungin, and 8 comparator antifungal agents’ susceptibility profiles for common and uncommon opportunistic fungi collected in 2013: temporal analysis of antifungal drug resistance using CLSI species-specific clinical breakpoints and proposed epidemiological cutoff values, Diagn Microbiol Infect Dis source
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- cites [32] Ying, 2015, Fluconazole susceptibility of 3,056 clinical isolates of Candida species from 2005 to 2009 in a tertiary-care hospital, Indian J Med Microbiol source
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Interpretationnone given§ IntroductionThe susceptibility pattern of various Candida species may vary depending upon prior antifungal drug exposure, health status of the patient, site of isolation and geographical location.
“The susceptibility pattern of various Candida species may also vary depending upon prior antifungal drug exposure, health status of the patient affected, site of isolation and geographical location.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ IntroductionOf the five major Candida species, C. krusei is the least common and is most often found among patients with underlying haematological malignancies with prior antifungal exposure.
“Of the five major Candida species, C. krusei is the least common and it is most often found among patients with underlying haematological malignancies with prior antifungal exposure.25 , 26”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [25] Hachem, 2008, The changing epidemiology of invasive candidiasis: Candida glabrata and Candida krusei as the leading causes of candidemia in hematologic malignancy, Cancer source
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- cites [26] Sipsas, 2009, Candidemia in patients with hematologic malignancies in the era of new antifungal agents (2001-2007): stable incidence but changing epidemiology of a still frequently lethal infection, Cancer source
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Interpretationnone given§ IntroductionAlthough azole resistance of naive C. albicans isolates is rare, a steady increase in reports of azole resistance, resulting in therapeutic failures, has been a matter of serious clinical concern.
“Although azole resistance of naive C. albicans isolates is rare, a steady increase in reports of azole resistance, resulting in therapeutic failures, has been a matter of serious clinical concern.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ IntroductionC. parapsilosis and/or C. tropicalis are much more frequently encountered than C. glabrata in Latin America, Southern Europe, India and Pakistan.
“However, C. parapsilosis and/or C. tropicalis are much more frequently encountered than C. glabrata in Latin America, Southern Europe, India and Pakistan.17 , 19–24”
Quote in the paperNot a substantial claim0 of 7 sources checked- cites [17] Castanheira, 2016, Antifungal susceptibility patterns of a global collection of fungal isolates: results of the SENTRY Antifungal Surveillance Program (2013), Diagn Microbiol Infect Dis source
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- cites [19] Pappas, 2018, Invasive candidiasis, Nat Rev Dis Primers source
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- cites [20] Tan, 2015, Incidence and species distribution of candidaemia in Asia: a laboratory-based surveillance study, Clin Microbiol Infect source
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- cites [21] Cheng, 2006, Risk factors for candidemia-related mortality at a medical center in central Taiwan, J Microbiol Immunol Infect
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- cites [22] Colombo, 2006, Epidemiology of candidemia in Brazil: a nationwide sentinel surveillance of candidemia in eleven medical centers, J Clin Microbiol source
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- cites [23] Chowdhary, 2003, An outbreak of candidemia due to Candida tropicalis in a neonatal intensive care unit, Mycoses source
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- cites [24] Farooqi, 2013, Invasive candidiasis in Pakistan: clinical characteristics, species distribution and antifungal susceptibility, J Med Microbiol source
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Premisecitation§ IntroductionC. glabrata tends to display high fluconazole MICs while retaining amphotericin B and echinocandin susceptibility.
“C. glabrata tends to display high fluconazole MICs, while retaining amphotericin B and echinocandin susceptibility;”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [17] Castanheira, 2016, Antifungal susceptibility patterns of a global collection of fungal isolates: results of the SENTRY Antifungal Surveillance Program (2013), Diagn Microbiol Infect Dis source
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- cites [27] Chowdhary, 2017, Candida auris: a rapidly emerging cause of hospital-acquired multidrug-resistant fungal infections globally, PLoS Pathog source
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- cites [36] Pfaller, 2014, Regional data analysis of Candida non-albicans strains collected in United States medical sites over a 6-year period, 2006-2011, Mycoses source
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- cites [37] Khan, 2019, Candida lusitaniae in Kuwait: prevalence, antifungal susceptibility and role in neonatal fungemia, PLoS One source
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ IntroductionBenign commensal colonization of C. albicans can become pathogenic due to shifts in pH and oxygen levels, alterations in host microbiota, or changes in host immune response.
“However, this benign commensal colonization can become pathogenic due to shifts in pH and oxygen levels, alterations in host microbiota (e.g. from antibiotic usage) or changes in the host immune response (e.g. during stress, infection by another microbe or immunosuppressant therapy).29”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Pfaller, 2007, Epidemiology of invasive candidiasis: a persistent public health problem, Clin Microbiol Rev source
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Premisecitation§ IntroductionCandida auris is an emerging MDR species globally.
“Another worrisome MDR species that is emerging globally is Candida auris.27”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [27] Chowdhary, 2017, Candida auris: a rapidly emerging cause of hospital-acquired multidrug-resistant fungal infections globally, PLoS Pathog source
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Premisecitation§ IntroductionThere has been considerable change in species distribution in recent years, dependent upon geographical location and patient population, with a decrease in the proportion of C. albicans and an increase in C. glabrata, C. parapsilosis and other non-albicans Candida species.
“It is pertinent to mention here that there has been considerable change in species distribution in recent years, dependent upon geographical location and patient population, with a decrease in the proportion of C. albicans and an increase in C. glabrata, C. parapsilosis and other non-albicans Candida species.16”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Whaley, 2016, Azole antifungal resistance in Candida albicans and emerging non-albicans Candida species, Front Microbiol
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Interpretationnone given§ IntroductionWhile antifungal resistance in C. albicans is relatively uncommon compared with species like C. glabrata, gradual use of fluconazole for long-term prophylaxis or treatment may lead to selective pressure resulting in emergence of secondary resistance in otherwise susceptible strains.
“While antifungal resistance in C. albicans is relatively uncommon as compared with species like C. glabrata, gradual use of fluconazole for long-term prophylaxis or treatment may lead to selective pressure resulting in emergence of secondary resistance in otherwise susceptible strains.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionC. auris is often MDR.
“the emerging fungal threat C. auris is often MDR.17 , 27 , 36 , 37”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [17] Castanheira, 2016, Antifungal susceptibility patterns of a global collection of fungal isolates: results of the SENTRY Antifungal Surveillance Program (2013), Diagn Microbiol Infect Dis source
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- cites [27] Chowdhary, 2017, Candida auris: a rapidly emerging cause of hospital-acquired multidrug-resistant fungal infections globally, PLoS Pathog source
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- cites [36] Pfaller, 2014, Regional data analysis of Candida non-albicans strains collected in United States medical sites over a 6-year period, 2006-2011, Mycoses source
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- cites [37] Khan, 2019, Candida lusitaniae in Kuwait: prevalence, antifungal susceptibility and role in neonatal fungemia, PLoS One source
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May combine two claims.
Premisecitation§ IntroductionABC transporters Cdr1 and Cdr2 have both been well documented as drivers of azole resistance and were first implicated in clinical azole resistance in isolates in HIV-infected patients with oropharyngeal candidiasis.
“The ATP-binding cassette (ABC) transporters Cdr1 and Cdr2 have both been well documented as drivers of azole resistance and were first implicated in clinical azole resistance in isolates in HIV-infected patients with oropharyngeal candidiasis.75–77”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [75] Prasad, 1995, Molecular cloning and characterization of a novel gene of Candida albicans, CDR1, conferring multiple resistance to drugs and antifungals, Curr Genet source
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- cites [76] Sanglard, 1997, Cloning of Candida albicans genes conferring resistance to azole antifungal agents: characterization of CDR2, a new multidrug ABC transporter gene, Microbiology source
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- cites [77] Sanglard, 1995, Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters, Antimicrob Agents Chemother source
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Premisecitation§ IntroductionA 22 year Norwegian national surveillance study of candidaemia found 98.8% of C. albicans isolates to be susceptible to fluconazole; however, only 0.25% of C. albicans isolates were fluconazole resistant during 2004-12.
“A 22 year Norwegian national surveillance study of candidaemia found 98.8% of C. albicans isolates to be susceptible to fluconazole; however, only 0.25% of C. albicans isolates were fluconazole resistant during 2004–12.69”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [69] Hesstvedt, 2015, Twenty-two years of candidaemia surveillance: results from a Norwegian national study, Clin Microbiol Infect source
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Premisenone given§ IntroductionVoriconazole is a triazole considered as an alternative or step-down therapy in many instances where fluconazole is also used.
“Voriconazole is another triazole considered as an alternative or step-down therapy in many instances where fluconazole is also used”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationcitation§ IntroductionOverall, global data suggest that C. albicans remains the predominant infective organism identified in Candida-based infections.
“Overall, the global data suggest that C. albicans remains the predominant infective organism identified in Candida-based infections.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionCurrently, antifungal therapy revolves around three main classes of antifungal drugs: the azole antifungals, echinocandins and polyene antifungals such as amphotericin B.
“Currently, antifungal therapy revolves around three main classes of antifungal drugs: the azole antifungals, echinocandins and polyene antifungals such as amphotericin B.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Pappas, 2016, Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America, Clin Infect Dis source
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ IntroductionSuperficial mucosal C. albicans infections pose a considerable threat in immunocompromised populations and high morbidity and mortality associated with serious invasive Candida infections continues to burden healthcare systems.
“However, superficial mucosal C. albicans infections pose a considerable threat in immunocompromised populations and the high morbidity and mortality associated with serious invasive Candida infections continues to burden our healthcare systems.72–74”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [72] Benedict, 2019, Estimation of direct healthcare costs of fungal diseases in the United States, Clin Infect Dis source
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- cites [73] Askinyte, 2015, Oral manifestations of HIV disease: a review, Stomatologija
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- cites [74] Redding, 1999, Epidemiology of oropharyngeal Candida colonization and infection in patients receiving radiation for head and neck cancer, J Clin Microbiol source
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Premisecitation§ IntroductionLow azole resistance rates of about 0.9% and ∼2% have been reported from Australia and South Africa from 2014 to 2015.
“However, low azole resistance rates of about 0.9% and ∼2% have been reported from Australia and South Africa from 2014 to 2015.71”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [71] Chapman, 2017, Changing epidemiology of candidaemia in Australia, J Antimicrob Chemother source
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Premisecitation§ IntroductionAnother Danish study reported a fluconazole resistance rate (defined by MIC >4 mg/L) of about 0.6% (7/1183 isolates).
“Another Danish study reported a fluconazole resistance rate (defined in this study by an MIC of >4 mg/L) of about 0.6% (7/1183 isolates).66”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [66] Arendrup, 2011, National surveillance of fungemia in Denmark (2004 to 2009), J Clin Microbiol source
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Premisecitation§ IntroductionVT-1161 is currently undergoing clinical trials as a treatment for recurrent vaginal candidiasis and may be a plausible future therapy against some azole-resistant C. albicans infections.
“VT-1161, more specifically, is currently undergoing clinical trials as a treatment for recurrent vaginal candidiasis and may be a plausible future therapy against some azole-resistant C. albicans infections.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationcitation§ IntroductionWhile reported resistance rates vary from study to study, collected surveillance data suggest that fluconazole resistance rates and azole resistance rates in general for C. albicans remain relatively low.
“While reported resistance rates vary from study to study, collected surveillance data suggest that fluconazole resistance rates and azole resistance rates in general for C. albicans remain relatively low.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ IntroductionIsavuconazonium sulphate is effective against Candida, including azole-resistant Candida species, but does not currently have a place in the treatment of invasive candidiasis and is reserved for serious mould infections such as aspergillosis and mucormycosis.
“The newly approved triazole prodrug isavuconazonium sulphate, while effective against Candida, including azole-resistant Candida species, does not currently have a place in the treatment of invasive candidiasis and is instead reserved for the serious mould infections such as aspergillosis and mucormycosis.51 , 52”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [51] Rybak, 2015, Isavuconazole: pharmacology, pharmacodynamics, and current clinical experience with a new triazole antifungal agent, Pharmacotherapy source
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- cites [52] Shirley, 2016, Isavuconazole: a review in invasive aspergillosis and mucormycosis, Drugs source
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Premisecitation§ IntroductionIn a study from Spain with C. albicans (45.4%) being the predominant species, about 1% of C. albicans strains were fluconazole resistant.
“Similarly, in a study from Spain with C. albicans (45.4%) being the predominant species, about 1% of C. albicans strains were fluconazole resistant.67”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [67] Puig-Asensio, 2014, Epidemiology and predictive factors for early and late mortality in Candida bloodstream infections: a population-based surveillance in Spain, Clin Microbiol Infect source
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Premisecitation§ IntroductionIn a 2015 study conducted in ICU centres across India, 5.2% of C. albicans strains sourced from ICU-acquired candidaemia were identified as fluconazole resistant.
“In a 2015 study conducted in ICU centres across India, 5.2% of C. albicans strains sourced from ICU-acquired candidaemia were identified as fluconazole resistant.70”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [70] Chakrabarti, 2015, Incidence, characteristics and outcome of ICU-acquired candidemia in India, Intensive Care Med source
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ IntroductionAbout 1.4% of C. albicans isolates were resistant to fluconazole, of which 63.6% were cross-resistant to voriconazole.
“About 1.4% of C. albicans isolates were resistant to fluconazole, of which 63.6% were cross-resistant to voriconazole.43”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [43] Pfaller, 2010, Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: a 10.5-year analysis of susceptibilities of Candida species to fluconazole and voriconazole as determined by CLSI standardized disk diffusion, J Clin Microbiol source
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Premisecitation§ IntroductionRecent updates to clinical practice guidelines now recommend the echinocandin class in many invasive Candida infections, but fluconazole remains a viable first-line alternative in many cases, such as in non-neutropenic patients with Candida bloodstream infection.
“While recent updates to clinical practice guidelines now recommend the echinocandin class of antifungals in many invasive Candida infections, fluconazole remains a viable first-line alternative in many cases, such as in non-neutropenic patients with Candida bloodstream infection.30”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Pappas, 2016, Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America, Clin Infect Dis source
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Premisecitation§ IntroductionSurveillance data analysing 1514 Candida species collected from Europe (41.0%), Asia Pacific (24.5%), North America (23.5%) and Latin America (11.0%) during 2013 determined azole antifungal resistance rates of about 0.4% and 0.3% in C. albicans against fluconazole and voriconazole, respectively.
“More broadly, surveillance data analysing 1514 Candida species collected from Europe (41.0%), the Asia Pacific region (24.5%), North America (23.5%) and Latin America (11.0%) during 2013 determined azole antifungal resistance rates of about 0.4% and 0.3% in C. albicans against fluconazole and voriconazole, respectively.17”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [17] Castanheira, 2016, Antifungal susceptibility patterns of a global collection of fungal isolates: results of the SENTRY Antifungal Surveillance Program (2013), Diagn Microbiol Infect Dis source
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Premisenone given§ IntroductionThe azole antifungals are among the most common therapies for treatment and prophylaxis of both superficial and invasive candidiasis.
“The azole antifungals are among the most common therapies for treatment and prophylaxis of both superficial and invasive candidiasis.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ IntroductionAccumulation of 14α-methylergosta-8,24(28)-dien-3β,6α-diol is toxic to the cell and results in the fungistatic effect seen with the azole antifungals.
“The accumulation of this compound is toxic to the cell and results in the fungistatic effect seen with the azole antifungals.50”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [50] Kelly, 1997, Resistance to fluconazole and cross-resistance to amphotericin B in Candida albicans from AIDS patients caused by defective sterol Δ5,6-desaturation, FEBS Letters source
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Premisenone given§ IntroductionThe mechanisms of azole resistance in Candida species have been extensively studied in C. albicans.
“The mechanisms of azole resistance in Candida species have been extensively studied in C. albicans.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionA surveillance study in Denmark evaluated 303 episodes of fungaemia and reported the predominance of C. albicans, followed by C. glabrata, C. tropicalis and C. parapsilosis.
“A surveillance study in Denmark evaluated 303 episodes of fungaemia and reported the predominance of C. albicans, followed by C. glabrata, C. tropicalis and C. parapsilosis.65”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [65] Arendrup, 2005, Seminational surveillance of fungemia in Denmark: notably high rates of fungemia and numbers of isolates with reduced azole susceptibility, J Clin Microbiol source
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Interpretationnone given§ IntroductionC. albicans and other Candida species have a variety of methods to survive even proper treatment practices.
“however, C. albicans and other Candida species have a variety of methods to survive even proper treatment practices.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionDecreased in vitro susceptibility of C. albicans to azoles such as miconazole, econazole, ketoconazole and clotrimazole has been recognized since the late 1970s.
“Decreased in vitro susceptibility of C. albicans to azoles such as miconazole, econazole, ketoconazole and clotrimazole has been recognized since the late 1970s.62 , 63”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ IntroductionAn azole resistance rate of about 2.3% in C. albicans bloodstream isolates was reported in a 2012 US study, where C. albicans was the most common species isolated, followed by C. glabrata, C. parapsilosis and C. tropicalis.
“For example, an azole resistance rate of about 2.3% in C. albicans bloodstream isolates was reported in a 2012 US study, where C. albicans was the most common species isolated, followed by C. glabrata, C. parapsilosis and C. tropicalis.64”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [64] Cleveland, 2012, Changes in incidence and antifungal drug resistance in candidemia: results from population-based laboratory surveillance in Atlanta and Baltimore, 2008-2011, Clin Infect Dis source
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Premisecitation§ IntroductionFlucytosine is used in the treatment of certain invasive Candida infections and cryptococcal meningitis, but is limited to combination therapies with amphotericin B.
“The antimetabolite pyrimidine analogue flucytosine is also used in the treatment of certain invasive Candida infections and cryptococcal meningitis, but is limited to combination therapies with amphotericin B.30”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Pappas, 2016, Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America, Clin Infect Dis source
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Premisecitation§ IntroductionBoth CLSI and EUCAST have established defined clinical breakpoints aimed to help predict outcomes for a given antifungal agent and organism.
“Additionally, both organizations have established defined clinical breakpoints aimed to help predict outcomes for a given antifungal agent and organism.60 , 61”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [60] 2018
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- cites [61] 2012
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Premisecitation§ IntroductionAbout 3.9% (n = 7) of C. albicans (n = 179) isolates were found to be fluconazole resistant in a multicentre study from Belgium during 2013-14.
“About 3.9% (n = 7) of C. albicans (n = 179) isolates were found be fluconazole resistant in a multicentre study from Belgium during 2013–14.68”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [68] Trouve, 2017, Epidemiology and reporting of candidaemia in Belgium: a multi-centre study, Eur J Clin Microbiol Infect Dis source
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Premisecitation§ IntroductionTetrazole compounds VT-1129, VT-1161 and VT-1598 are currently awaiting or undergoing clinical trials to treat a wide variety of fungal infections.
“The tetrazole compounds, VT-1129, VT-1161 and VT-1598, so named because of an additional nitrogen on the five-membered azole ring that defines the class, are currently awaiting or undergoing clinical trials to treat a wide variety of fungal infections.53 , 54”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [53] Wiederhold, 2018, In vivo efficacy of VT-1129 against experimental cryptococcal meningitis with the use of a loading dose-maintenance dose administration strategy, Antimicrob Agents Chemother source
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- cites [54] Nishimoto, 2019, In vitro activities of the novel investigational tetrazoles VT-1161 and VT-1598 compared to the triazole antifungals against azole-resistant strains and clinical isolates of Candida albicans, Antimicrob Agents Chemother source
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Premisenone given§ IntroductionThe triazoles itraconazole and posaconazole have niche uses in invasive candidiasis, such as alternatives for oropharyngeal or oesophageal candidiasis in fluconazole-refractory disease.
“the triazoles itraconazole and posaconazole have niche uses in invasive candidiasis, such as alternatives for oropharyngeal or oesophageal candidiasis in fluconazole-refractory disease.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisenone given§ IntroductionMost data related to the prevalence of triazole resistance in Candida species originates primarily from studies carried out in the USA and Europe.
“Most of the data related to the prevalence of triazole resistance in Candida species originates primarily from studies carried out in the USA and Europe.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisereasoning§ IntroductionAs no oral echinocandin is currently available commercially, fluconazole and other triazoles are important for outpatient and step-down therapies for prophylaxis and treatment.
“Additionally, as no oral echinocandin is currently available commercially, fluconazole and the other triazoles are important for outpatient and step-down therapies for prophylaxis and treatment.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Premisenone given§ IntroductionEmergence of azole resistance in Candida species, especially those originating from patients on prolonged azole therapy, has become a worldwide problem.
“Emergence of azole resistance in Candida species, especially those originating from patients on prolonged azole therapy, have become a worldwide problem thereby stressing the need for antifungal stewardship.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ IntroductionDeletion of MRR1 in MDR1-overexpressing isolates F5 and G5 abolished MDR1 promoter activity in a PMDR1-GFP reporter fusion, implicating Mrr1 in the constitutive expression of MDR1 in these fluconazole-resistant clinical isolates.
“Deletion of MRR1 in MDR1-overexpressing isolates F5 and G5 managed to abolish MDR1 promoter activity in a PMDR1-GFP reporter fusion, implicating Mrr1 in the constitutive expression of MDR1 in these fluconazole-resistant clinical isolates.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [103] Morschhauser, 2007, The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans, PLoS Pathog source
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Premisecitation§ IntroductionDeletion of MDR1 alone in both cases resulted in a higher MIC in the resistant clinical isolate background compared with deletion of its transcriptional regulator Mrr1, providing evidence that Mrr1 may regulate other determinants of fluconazole resistance apart from Mdr1.
“Deletion of MDR1 alone in both cases resulted in a higher MIC in the resistant clinical isolate background compared with deletion of its transcriptional regulator Mrr1, providing evidence that Mrr1 may regulate other determinants of fluconazole resistance apart from Mdr1.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [103] Morschhauser, 2007, The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans, PLoS Pathog source
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Premisecitation§ IntroductionWhen the MDR1 gene was disrupted in two fluconazole-resistant clinical C. albicans isolates, susceptibility to fluconazole increased compared with resistant isolates with intact MDR1, demonstrating a direct relationship between MDR1 and fluconazole resistance in clinical isolates.
“When the MDR1 gene was disrupted in two fluconazole-resistant clinical C. albicans isolates, susceptibility to fluconazole increased compared with the resistant isolates with intact MDR1, demonstrating a direct relationship between MDR1 and fluconazole resistance in clinical isolates.100”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [100] Wirsching, 2000, Targeted gene disruption in Candida albicans wild-type strains: the role of the MDR1 gene in fluconazole resistance of clinical Candida albicans isolates, Mol Microbiol source
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Premisecitation§ IntroductionMdr1, part of the MFS of transporters, plays a role in fluconazole and voriconazole resistance, though it does not effect large MIC changes with other azole antifungals such as itraconazole, isavuconazole and posaconazole.
“Mdr1, part of the major facilitator superfamily (MFS) of transporters (Figure 1g), has also been shown to play a role in fluconazole and voriconazole resistance, though it does not effect large MIC changes with other azole antifungals such as itraconazole, isavuconazole and posaconazole.93–95”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [93] Sanglard, 2016, Activity of isavuconazole and other azoles against Candida clinical isolates and yeast model systems with known azole resistance mechanisms, Antimicrob Agents Chemother source
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- cites [94] Xiao, 2004, Three-dimensional models of wild-type and mutated forms of cytochrome P450 14α-sterol demethylases from Aspergillus fumigatus and Candida albicans provide insights into posaconazole binding, Antimicrob Agents Chemother source
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- cites [95] Cheng, 2007, A Candida albicans petite mutant strain with uncoupled oxidative phosphorylation overexpresses MDR1 and has diminished susceptibility to fluconazole and voriconazole, Antimicrob Agents Chemother source
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Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionA more recent study found no increase in CDR1 or CDR2 expression as measured by RT-qPCR in the presence of fluconazole in a C. albicans strain with 6His3Flag-tagged Tac1.
“a more recent study found that no increase in CDR1 or CDR2 expression as measured by quantitative reverse transcription PCR (RT–qPCR) could be observed in the presence of fluconazole in a C. albicans strain with 6His3Flag-tagged Tac1.89 , 90”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [89] Hernaez, 1998, Induced expression of the Candida albicans multidrug resistance gene CDR1 in response to fluconazole and other antifungals, Yeast source
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- cites [90] Liu, 2017, Mediator tail module is required for Tac1-activated CDR1 expression and azole resistance in Candida albicans, Antimicrob Agents Chemother source
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Premisecitation§ IntroductionInduction of MDR1 mRNA expression through benomyl and tert-butyl hydrogen peroxide identified several cis-acting elements in the MDR1 promoter involved in induction with these agents, though fluconazole itself failed to induce the MDR1 promoter.
“Induction of MDR1 mRNA expression through benomyl and tert-butyl hydrogen peroxide identified several cis-acting elements in the MDR1 promoter involved in induction with these agents, though fluconazole itself failed to induce the MDR1 promoter.102”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [102] Harry, 2005, Drug-induced regulation of the MDR1 promoter in Candida albicans, Antimicrob Agents Chemother source
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Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionThe gene encoding the Mdr1 efflux pump in C. albicans was originally discovered by its ability to confer resistance to several structurally unrelated compounds in S. cerevisiae expressing the C. albicans MDR1 gene.
“The gene encoding the Mdr1 efflux pump in C. albicans was originally discovered by its ability to confer resistance to several structurally unrelated compounds such as the anti-mitotic drug benomyl, methotrexate, cycloheximide, sulfometuron methyl, 4-nitroquinoline-N-oxide and bentriazoles in Saccharomyces cerevisiae expressing the C. albicans MDR1 gene, which at the time was known as BENr.96 , 97”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [96] Fling, 1991, Analysis of a Candida albicans gene that encodes a novel mechanism for resistance to benomyl and methotrexate, Mol Gen Genet source
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- cites [97] Ben-Yaacov, 1994, Candida albicans gene encoding resistance to benomyl and methotrexate is a multidrug resistance gene, Antimicrob Agents Chemother source
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Premisecitation§ IntroductionWhile CDR2 deletion also reduced resistance to fluconazole and ketoconazole, the effect was much weaker compared with CDR1 deletion, suggesting Cdr1 is the major contributor towards Tac1-mediated azole resistance.
“While CDR2 deletion also reduced resistance to fluconazole and ketoconazole, the effect was much weaker compared with CDR1 deletion, suggesting Cdr1 is the major contributor towards Tac1-mediated azole resistance.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [84] Tsao, 2009, Relative contributions of the Candida albicans ABC transporters Cdr1p and Cdr2p to clinical azole resistance, Antimicrob Agents Chemother source
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Premisecitation§ IntroductionIn patients with recurrent oropharyngeal candidiasis treated with fluconazole, increased MDR1 mRNA, as well as increased CDR1/2 and ERG11 gene expression, correlated with increasing fluconazole drug resistance, indicating MDR1 plays a role in the multifaceted development of resistance in C. albicans.
“A study assessing sequential isolates of C. albicans in patients with recurrent oropharyngeal candidiasis treated with fluconazole found that increased MDR1 mRNA, as well as increased CDR1/2 and ERG11 gene expression, correlated with increasing fluconazole drug resistance, indicating that MDR1 plays a role in the multifaceted development of resistance in C. albicans.99”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [99] Lopez-Ribot, 1998, Distinct patterns of gene expression associated with development of fluconazole resistance in serial Candida albicans isolates from human immunodeficiency virus-infected patients with oropharyngeal candidiasis, Antimicrob Agents Chemother source
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Premisecitation§ IntroductionTac1-driven transcription of CDR1 is decreased in gain-of-function Tac1 mutant strains lacking either Med3 or Med15, and deletion of MED3 also diminishes xenobiotic-induced expression levels of CDR1, CDR2 and RTA3 with fluphenazine and oestradiol.
“Furthermore, not only was Tac1-driven transcription of CDR1 decreased in gain-of-function Tac1 mutant strains lacking either Med3 or Med15, but deletion of MED3 also diminished xenobiotic-induced expression levels of CDR1, CDR2 and RTA3 with fluphenazine and oestradiol.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [90] Liu, 2017, Mediator tail module is required for Tac1-activated CDR1 expression and azole resistance in Candida albicans, Antimicrob Agents Chemother source
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Premisecitation§ IntroductionPresence of DREs within each gene's promoter regions contributes to induced and constitutive expression of CDR1 and CDR2, while a separate BEE contributes to CDR1 baseline expression.
“The presence of drug-responsive elements (DREs) within each gene’s respective promoter regions, for example, has been shown to contribute to the induced and constitutive expression of CDR1 and CDR2, while a separate basal expression element (BEE) contributes to CDR1 baseline expression.80 , 88 , 92”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [80] Coste, 2004, TAC1, transcriptional activator of CDR genes, is a new transcription factor involved in the regulation of Candida albicans ABC transporters CDR1 and CDR2, Eukaryot Cell source
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- cites [88] de Micheli, 2002, A common drug-responsive element mediates the upregulation of the Candida albicans ABC transporters CDR1 and CDR2, two genes involved in antifungal drug resistance, Mol Microbiol source
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- cites [92] Liu, 2007, Genome-wide expression and location analyses of the Candida albicans Tac1p regulon, Eukaryot Cell source
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Premisecitation§ IntroductionIn matched azole-susceptible versus azole-resistant isolates from the same patient, constitutive high expression of these transporters was suggested to be a result of both increased transcription and increased mRNA stability, the latter tied to mRNA hyperadenylation and loss of heterozygosity at the poly(A) polymerase 1 locus.
“In a comparison of azole-susceptible versus azole-resistant matched isolates from the same patient, constitutive high expression of these transporters was suggested to be a result of both increased transcription and increased mRNA stability, the latter of which is tied to mRNA hyperadenylation and loss of heterozygosity at the poly(A) polymerase 1 locus.82 , 83”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [82] Manoharlal, 2008, Transcriptional activation and increased mRNA stability contribute to overexpression of CDR1 in azole-resistant Candida albicans, Antimicrob Agents Chemother source
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- cites [83] Manoharlal, 2010, PAP1 [poly(A) polymerase 1] homozygosity and hyperadenylation are major determinants of increased mRNA stability of CDR1 in azole-resistant clinical isolates of Candida albicans, Microbiology (Reading, Engl) source
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Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionIncreased CDR1 expression can be induced in the presence of agents such as oestradiol or fluphenazine.
“Additionally, it was shown that increased CDR1 expression could be induced in the presence of agents such as oestradiol or fluphenazine.88”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [88] de Micheli, 2002, A common drug-responsive element mediates the upregulation of the Candida albicans ABC transporters CDR1 and CDR2, two genes involved in antifungal drug resistance, Mol Microbiol source
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Premisecitation§ IntroductionIn genome-wide location analysis of Tac1 binding sites using ChIP-chip, Tac1 binds to the DRE of both CDR1 and CDR2 under non-activating conditions, indicating post-binding mechanisms such as repressor interaction loss or co-activator recruitment may occur during Tac1 activation.
“In a genome-wide location analysis of Tac1 binding sites using ChIP-chip, Tac1 was shown to bind to the DRE of both CDR1 and CDR2 under non-activating conditions, indicating that post-binding mechanisms such as repressor interaction loss or co-activator recruitment may occur during Tac1 activation.92”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [92] Liu, 2007, Genome-wide expression and location analyses of the Candida albicans Tac1p regulon, Eukaryot Cell source
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Premisecitation§ IntroductionChIP assays revealed occupancy of the mediator tail module at the CDR1 DRE increases during Tac1 hyperactivation, as well as with TAC1 overexpression; however, higher occupancy at the DRE did not result in increased fluconazole MICs, unless Tac1 was activated.
“ChIP assays revealed that occupancy of the mediator tail module at the CDR1 DRE increases during Tac1 hyperactivation, as well as with TAC1 overexpression; however, higher occupancy at the DRE did not result in increased fluconazole MICs, unless Tac1 was activated.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [90] Liu, 2017, Mediator tail module is required for Tac1-activated CDR1 expression and azole resistance in Candida albicans, Antimicrob Agents Chemother source
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Premisecitation§ IntroductionMutations in the ERG11 gene itself are another common azole resistance mechanism in C. albicans, in stark contrast to the haploid organism C. glabrata, in which the frequency of mutations in ERG11 appears relatively low.
“Mutations in the ERG11 gene itself are another common azole resistance mechanism in C. albicans (Figure 1b and c), in stark contrast to the haploid organism C. glabrata, in which the frequency of mutations in ERG11 appears relatively low.16 , 119”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [16] Whaley, 2016, Azole antifungal resistance in Candida albicans and emerging non-albicans Candida species, Front Microbiol
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- cites [119] Sanguinetti, 2005, Mechanisms of azole resistance in clinical isolates of Candida glabrata collected during a hospital survey of antifungal resistance, Antimicrob Agents Chemother source
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Premiseown data§ IntroductionThrough analysis of marker polymorphisms along chromosome 3 distal to MRR1 and proximal to the telomere, loss of heterozygosity with selection of mutated MRR1 alleles was accomplished through mitotic recombination in clinical isolates, though chromosome loss was also observed as a cause in MDR1-overexpressing strains developed in vitro.
“Through analysis of marker polymorphisms along chromosome 3 distal to MRR1 and proximal to the telomere, it was shown that loss of heterozygosity with selection of mutated MRR1 alleles was accomplished through mitotic recombination in clinical isolates, though chromosome loss was also observed as a cause in MDR1-overexpressing strains developed in vitro.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ IntroductionTwo 7 bp inverted-repeat sequences located −231 and −251 bp upstream of the start codon form an azole-responsive element (ARE) regulated by Upc2, and this ARE is sufficient to induce ERG11 expression.
“Furthermore, investigation of the ERG11 promoter through deletion and linker scan mutations concluded that two 7 bp inverted-repeat sequences located −231 and −251 bp upstream of the start codon form an azole-responsive element (ARE) regulated by Upc2 and that this ARE was sufficient to induce ERG11 expression.108”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [108] Oliver, 2007, cis-Acting elements within the Candida albicans ERG11 promoter mediate the azole response through transcription factor Upc2p, Eukaryot Cell source
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Premisecitation§ IntroductionIn hyperactive ZCF strains, Znc1 and Mrr2 appeared to activate the CDR1 promoter, indicating that these ZCFs may contribute to increased efflux pump expression.
“Additionally, in the hyperactive ZCF strains, Znc1 and Mrr2 appeared to activate the CDR1 promoter, indicating that these ZCFs may contribute to increased efflux pump expression.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [116] Schillig, 2013, Analysis of a fungus-specific transcription factor family, the Candida albicans zinc cluster proteins, by artificial activation, Mol Microbiol source
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Premisecitation§ IntroductionWhen UPC2 was disrupted, Δupc2 mutants had decreased cellular ergosterol content and were more susceptible to fluconazole not only in the azole-susceptible SC5314 strain but also in a highly resistant clinical isolate 12-99, which overexpresses CDR1, MDR1 and ERG11 and possesses a mutation in ERG11, suggesting that UPC2 is required for clinical azole drug resistance.
“When UPC2 was disrupted, the Δupc2 mutants had decreased cellular ergosterol content and were more susceptible to fluconazole not only in the azole-susceptible SC5314 strain but also in a highly resistant clinical isolate 12–99, which overexpresses CDR1, MDR1 and ERG11 and possesses a mutation in ERG11, suggesting that UPC2 is required for clinical azole drug resistance.114 , 115”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [114] Flowers, 2012, Gain-of-function mutations in UPC2 are a frequent cause of ERG11 upregulation in azole-resistant clinical isolates of Candida albicans, Eukaryot Cell source
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- cites [115] Vasicek, 2014, UPC2 is universally essential for azole antifungal resistance in Candida albicans, Eukaryot Cell source
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Premisecitation§ IntroductionMultiple additional amino acid substitutions in Erg11 were uncovered and the effect of these amino acid changes on triazole antifungal MICs was not uniform.
“Soon after, multiple additional amino acid substitutions in Erg11 were uncovered and, notably, the effect of these amino acid changes on triazole antifungal MICs was not uniform.121”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [121] Sanglard, 1998, Amino acid substitutions in the cytochrome P-450 lanosterol 14α-demethylase (CYP51A1) from azole-resistant Candida albicans clinical isolates contribute to resistance to azole antifungal agents, Antimicrob Agents Chemother source
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Premiseown data§ IntroductionThrough DNA sequence analysis of the F1-F5 matched-series clinical isolates, gain-of-function mutations appear to occur in a single MRR1 allele initially, which provides an intermediate level of resistance compared with matched isolates collected chronologically later in the series that were homozygous for the MRR1 P683S allele.
“Furthermore, through DNA sequence analysis of the F1–F5 matched-series clinical isolates, it was revealed that gain-of function mutations appear to occur in a single MRR1 allele initially, which provides an intermediate level of resistance compared with the matched isolates collected chronologically later in the series that were homozygous for the MRR1 P683S allele.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionA recent report investigating these mutations in MRR2 when inserted into the native locus, as well as when the gene is overexpressed, failed to identify any changes in fluconazole susceptibility or CDR1 expression compared with WT.
“In contrast to this finding, a recent report investigating these mutations in MRR2 when inserted into the native locus, as well as when the gene is overexpressed, failed to identify any changes in fluconazole susceptibility or CDR1 expression compared with WT.118”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [118] Nishimoto, 2019, The contribution of clinically-derived mutations in the gene encoding the zinc cluster transcription factor Mrr2 to fluconazole antifungal resistance and CDR1 expression in Candida albicans, Antimicrob Agents Chemother source
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Premisecitation§ IntroductionAs azole antifungals emerged as a common first-line option, documentation of new ERG11 mutations in azole-resistant clinical isolates continued to appear, though not all documented mutations were definitively shown to be tied to azole resistance.
“As the azole antifungals emerged as a common first-line option in the treatment of many superficial and invasive fungal infections, documentation of new ERG11 mutations in azole-resistant clinical isolates continued to appear, though not all documented mutations were definitively shown to be tied to azole resistance.124–137”
Quote in the paperNot a substantial claim0 of 10 sources checked- cites [124] Wang, 2005, Analysis of ERG11 gene mutation in Candida albicans, Di Yi Jun Yi Da Xue Xue Bao
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- cites [125] Xu, 2008, Susceptibility of clinical isolates of Candida species to fluconazole and detection of Candida albicans ERG11 mutations, J Antimicrob Chemother source
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- cites [126] Wang, 2009, Rapid detection of ERG11 gene mutations in clinical Candida albicans isolates with reduced susceptibility to fluconazole by rolling circle amplification and DNA sequencing, BMC Microbiol source
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- cites [127] Feng, 2010, Relationship between antifungal resistance of fluconazole resistant Candida albicans and mutations in ERG11 gene, Chin Med J (Engl) source
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- cites [128] Kim, 2010, Evaluation of the V404I and V509M amino acid substitutions of ERG11 gene in Candida albicans isolates by pyrosequencing, Folia Microbiol (Praha) source
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- cites [129] Martel, 2010, A clinical isolate of Candida albicans with mutations in ERG11 (encoding sterol 14α-demethylase) and ERG5 (encoding C22 desaturase) is cross resistant to azoles and amphotericin B, Antimicrob Agents Chemother source
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- cites [130] Morio, 2010, Screening for amino acid substitutions in the Candida albicans Erg11 protein of azole-susceptible and azole-resistant clinical isolates: new substitutions and a review of the literature, Diagn Microbiol Infect Dis source
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- cites [131] Oliveira Carvalho, 2013, The new mutation L321F in Candida albicans ERG11 gene may be associated with fluconazole resistance, Rev Iberoam Micol source
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- cites [132] Strzelczyk, 2013, Nucleotide substitutions in the Candida albicans ERG11 gene of azole-susceptible and azole-resistant clinical isolates, Acta Biochim Pol source
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- cites [133] Xiang, 2013, Erg11 mutations associated with azole resistance in clinical isolates of Candida albicans, FEMS Yeast Res source
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Interpretationreasoning§ IntroductionGiven the contradictory findings, the clinical impact of other ZCFs outside of Tac1, Mrr1 and Upc2 in azole resistance remains in question.
“Given the contradictory findings, the clinical impact of other ZCFs outside of Tac1, Mrr1 and Upc2 in azole resistance remains in question.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ IntroductionLaboratory strains exhibiting hyperactive transcription factors Aro80, Mrr2, Stb5, Cta4, Zcf25, Zcf35 and Znc1 have displayed increased azole MICs comparable to hyperactive Tac1, Mrr1 and Upc2, demonstrating that in theory other ZCFs may play a role in azole resistance in C. albicans.
“Laboratory strains exhibiting hyperactive transcription factors Aro80, Mrr2, Stb5, Cta4, Zcf25, Zcf35 and Znc1 have also displayed increased azole MICs comparable to hyperactive Tac1, Mrr1 and Upc2, demonstrating that in theory other ZCFs may play a role in azole resistance in C. albicans.116”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [116] Schillig, 2013, Analysis of a fungus-specific transcription factor family, the Candida albicans zinc cluster proteins, by artificial activation, Mol Microbiol source
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Premisecitation§ IntroductionReplacement of a single copy of the mutant MRR1 allele encoding either a P683S or G997V amino acid substitution into SC5314 lacking both native copies of MRR1 resulted in increased resistance to fluconazole and increased MDR1 promoter activity as measured by a PMDR1-GFP reporter construct, demonstrating the presence of gain-of-function mutations in MRR1 that regulate MDR1 expression in C. albicans
“Replacement of a single copy of the mutant MRR1 allele encoding either a P683S or G997V amino acid substitution into SC5314 lacking both native copies of MRR1 resulted in increased resistance to fluconazole and increased MDR1 promoter activity as measured by a PMDR1-GFP reporter construct, demonstrating the presence of gain-of-function mutations in MRR1 that regulate MDR1 expression in C. albicans”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [103] Morschhauser, 2007, The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans, PLoS Pathog source
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Premisecitation§ IntroductionUpc2 is a Zn(II)-Cys(6) transcription factor involved in sterol biosynthesis and azole resistance.
“Upc2 is another Zn(II)-Cys(6) transcription factor involved in sterol biosynthesis and azole resistance.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ IntroductionInduction of ERG11 is abolished when UPC2 is deleted, and the deletion strain is hypersusceptible to azole drugs, as well as terbinafine, fenpropimorph and lovastatin, illustrating UPC2's important role in sterol biosynthesis regulation.
“However, not only was the induction of ERG11 abolished when UPC2 was deleted, but the deletion strain was also hypersusceptible to the azole drugs, as well as the squalene epoxidase (Erg1) target drug terbinafine, the Erg2 and Erg24 target drug fenpropimorph and the HMG-CoA reductase inhibitor lovastatin, illustrating UPC2’s important role in sterol biosynthesis regulation.105 , 107”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [105] Silver, 2004, Role of Candida albicans transcription factor Upc2p in drug resistance and sterol metabolism, Eukaryot Cell source
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- cites [107] MacPherson, 2005, Candida albicans zinc cluster protein Upc2p confers resistance to antifungal drugs and is an activator of ergosterol biosynthetic genes, Antimicrob Agents Chemother source
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Premisecitation§ IntroductionThe DNA-binding domain of Upc2 binds directly to ergosterol biosynthesis genes, binding to a putative sterol responsive element in ERG2.
“and it was also demonstrated that the DNA-binding domain of Upc2 bound directly to ergosterol biosynthesis genes, binding to a putative sterol responsive element in ERG2.107”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [107] MacPherson, 2005, Candida albicans zinc cluster protein Upc2p confers resistance to antifungal drugs and is an activator of ergosterol biosynthetic genes, Antimicrob Agents Chemother source
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Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionThe earliest point mutation resulting in an amino acid substitution (R467K) in the ERG11 gene of a clinical isolate was sequenced and discovered in 1997.
“The earliest point mutation resulting in an amino acid substitution (R467K) in the ERG11 gene of a clinical isolate was sequenced and discovered in 1997.120”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [120] White, 1997, The presence of an R467K amino acid substitution and loss of allelic variation correlate with an azole-resistant lanosterol 14alpha demethylase in Candida albicans, Antimicrob Agents Chemother source
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Interpretationreasoning§ IntroductionErg11 amino acid substitutions may contribute to azole resistance through more nuanced ways than simply reducing azole binding affinity.
“making it conceivable that Erg11 amino acid substitutions may contribute to azole resistance through more nuanced ways than simply reducing azole binding affinity.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ IntroductionAneuploidy plays a role in azole resistance and genetic diversity in C. albicans.
“Aneuploidy plays a role in azole resistance, as well as genetic diversity in C. albicans”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [150] Perepnikhatka, 1999, Specific chromosome alterations in fluconazole-resistant mutants of Candida albicans, J Bacteriol source
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- cites [151] Chen, 2004, Chromosome 1 trisomy compromises the virulence of Candida albicans, Mol Microbiol source
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Premisecitation§ IntroductionGain or loss of chromosomes is tied to azole resistance and attenuated virulence.
“Gain or loss of chromosomes has been tied to azole resistance and attenuated virulence.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [150] Perepnikhatka, 1999, Specific chromosome alterations in fluconazole-resistant mutants of Candida albicans, J Bacteriol source
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- cites [151] Chen, 2004, Chromosome 1 trisomy compromises the virulence of Candida albicans, Mol Microbiol source
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Probably not a substantial claim: may not pass S1 (asserted). May combine two claims.
Interpretationreasoning§ Introduction14α-Methylergosta-8,24(28)-dien-3β,6α-diol is toxic to C. albicans cells and its accumulation results in growth inhibition.
“the current belief that 14α-methylergosta-8,24(28)-dien-3β,6α-diol is toxic to the C. albicans cell and its accumulation results in the inhibition of growth.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone given§ IntroductionOverrepresentation of efflux pumps, ERG11 or ZCF genes involved in azole resistance as a result of chromosomal non-disjunctions, trisomy or isochromosome formation is very likely to contribute to decreased drug resistance in these cells.
“Overrepresentation of efflux pumps, ERG11 or ZCF genes involved in azole resistance as a result of chromosomal non-disjunctions, trisomy or isochromosome formation is very likely to contribute to decreased drug resistance in these cells.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ IntroductionIsolates with an ERG3 resistance phenotype display hyphal growth defects and attenuated virulence.
“isolates with an ERG3 resistance phenotype also displayed hyphal growth defects and attenuated virulence.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [146] Miyazaki, 2006, Fluconazole treatment is effective against a Candida albicans erg3/erg3 mutant in vivo despite in vitro resistance, Antimicrob Agents Chemother source
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- cites [147] Vale-Silva, 2012, Azole resistance by loss of function of the sterol Δ5,6-desaturase gene (ERG3) in Candida albicans does not necessarily decrease virulence, Antimicrob Agents Chemother source
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- cites [148] Chau, 2005, Inactivation of sterol Δ5,6-desaturase attenuates virulence in Candida albicans, Antimicrob Agents Chemother source
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Premisecitation§ IntroductionMaximal accumulation of fluconazole did not progress in a temperature-dependent manner, inconsistent with simple passive diffusion.
“maximal accumulation of fluconazole did not progress in a temperature-dependent manner, inconsistent with simple passive diffusion.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [160] Mansfield, 2010, Azole drugs are imported by facilitated diffusion in Candida albicans and other pathogenic fungi, PLoS Pathog source
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Interpretationcitation§ IntroductionThis mechanism of fluconazole import is likely conserved across many fungal species.
“this mechanism is likely conserved across many fungal species.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [160] Mansfield, 2010, Azole drugs are imported by facilitated diffusion in Candida albicans and other pathogenic fungi, PLoS Pathog source
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- cites [161] Esquivel, 2015, Azole drug import into the pathogenic fungus Aspergillus fumigatus, Antimicrob Agents Chemother source
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Premisecitation§ IntroductionHsp90 is involved in regulation of PKC signalling, which is involved in activation of calcineurin pathway and subsequent drug-induced stress response to azoles.
“Hsp90 has been shown to be involved in the regulation of protein kinase C (PKC) signalling, which is involved in the activation of the calcineurin pathway and subsequent drug-induced stress response to the azoles.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [166] LaFayette, 2010, PKC signaling regulates drug resistance of the fungal pathogen Candida albicans via circuitry comprised of Mkc1, calcineurin, and Hsp90, PLoS Pathog source
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Premisecitation§ IntroductionVarious factors including high fungal cell density, reduction in growth rate, lack of nutrition availability, production of extracellular exopolysaccharide matrix, presence of persister cells, gene expression alterations, and alterations in membrane sterol content influence Candida biofilm drug resistance.
“Various studies have described the influence of high fungal cell density, reduction in growth rate, lack of nutrition availability, production of extracellular exopolysaccharide matrix, presence of recalcitrant ‘persister’ cells that exhibit tolerance to antifungal drugs, gene expression alterations and alterations in membrane sterol content on the Candida cell membrane in this setting.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ IntroductionIn 43 clinical C. albicans isolates, loss-of-heterozygosity events were persistent and often associated with resistance, while aneuploidies were often transient and did not correlate with drug resistance.
“Recent analysis of large-scale genomic changes in 43 clinical isolates of C. albicans showed that, while loss-of-heterozygosity events were persistent and often associated with resistance, aneuploidies in clinical isolates were often transient and did not correlate with drug resistance.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [156] Ford, 2015, The evolution of drug resistance in clinical isolates of Candida albicans, Elife source
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Premisecitation§ IntroductionTrisomy of chromosome R and chromosome 4 possibly confers azole resistance in two different clinical isolates of C. albicans.
“The recent investigations into trisomy of chromosome R and chromosome 4 possibly conferring azole resistance in two different clinical isolates of C. albicans”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [117] Li, 2015, Trisomy of chromosome R confers resistance to triazoles in Candida albicans, Med Mycol source
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- cites [159] Anderson, 2017, A chromosome 4 trisomy contributes to increased fluconazole resistance in a clinical isolate of Candida albicans, Microbiology source
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Premisecitation§ IntroductionHsp90 is involved in the folding of a diverse set of client proteins and the regulation of signal transduction pathways.
“Hsp90 is involved in the folding of a diverse set of client proteins and the regulation of signal transduction pathways”
Quote in the paperNot a substantial claim0 of 6 sources checked- cites [162] Cowen, 2008, The evolution of fungal drug resistance: modulating the trajectory from genotype to phenotype, Nat Rev Microbiol source
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- cites [163] Cowen, 2006, Genetic architecture of Hsp90-dependent drug resistance, Eukaryot Cell source
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- cites [164] Cowen, 2005, Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi, Science source
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- cites [165] Singh, 2009, Hsp90 governs echinocandin resistance in the pathogenic yeast Candida albicans via calcineurin, PLoS Pathog source
Not checked in the free run.
- cites [166] LaFayette, 2010, PKC signaling regulates drug resistance of the fungal pathogen Candida albicans via circuitry comprised of Mkc1, calcineurin, and Hsp90, PLoS Pathog source
Not checked in the free run.
- cites [167] Cowen, 2009, Hsp90 orchestrates stress response signaling governing fungal drug resistance, PLoS Pathog source
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionCertain efflux pumps in planktonic cells are up-regulated within the first few hours of surface contact with azole antifungals and remain up-regulated throughout biofilm development.
“Certain efflux pumps in planktonic cells are often up-regulated within the first few hours of surface contact with azole antifungals and remain up-regulated throughout the biofilm development.”
Quote in the paperNot a substantial claim0 of 5 sources checked- cites [170] Mateus, 2004, Adherence of Candida albicans to silicone induces immediate enhanced tolerance to fluconazole, Antimicrob Agents Chemother source
Not checked in the free run.
- cites [171] Mukherjee, 2003, Mechanism of fluconazole resistance in Candida albicans biofilms: phase-specific role of efflux pumps and membrane sterols, Infect Immun source
Not checked in the free run.
- cites [172] Nett, 2009, Time course global gene expression analysis of an in vivo Candida biofilm, J Infect Dis source
Not checked in the free run.
- cites [173] Nobile, 2012, A recently evolved transcriptional network controls biofilm development in Candida albicans, Cell source
Not checked in the free run.
- cites [174] Ramage, 2002, Investigation of multidrug efflux pumps in relation to fluconazole resistance in Candida albicans biofilms, J Antimicrob Chemother source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone given§ IntroductionThere is limited evidence that reduced azole uptake has clinical relevance to azole resistance in C. albicans or any other Candida species.
“Currently there is limited evidence suggesting that reduced azole uptake has any clinical relevance to azole resistance in C. albicans or any other Candida species.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ IntroductionFoG does not correlate with growth rate or colony size.
“FoG did not correlate with growth rate or colony size”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [194] Rosenberg, 2018, Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia, Nat Commun source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ IntroductionTrailing growth phenomenon is related to azole tolerance and has been well documented in C. albicans.
“The ‘trailing growth’ phenomenon, describing the residual population of cells that grow at supra-MIC levels observed in broth dilution assays, can be considered related to azole tolerance and has been well documented in C. albicans.”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [184] Delarze, 2015, Defining the frontiers between antifungal resistance, tolerance and the concept of persistence, Drug Resist Updat source
Not checked in the free run.
- cites [185] Marchetti, 2000, Potent synergism of the combination of fluconazole and cyclosporine in Candida albicans, Antimicrob Agents Chemother source
Not checked in the free run.
- cites [186] Arthington-Skaggs, 2002, Comparison of visual and spectrophotometric methods of broth microdilution MIC end point determination and evaluation of a sterol quantitation method for in vitro susceptibility testing of fluconazole and itraconazole against trailing and nontrailing Candida isolates, Antimicrob Agents Chemother source
Not checked in the free run.
- cites [187] Lee, 2004, Drug resistance genes and trailing growth in Candida albicans isolates, J Antimicrob Chemother source
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionFoG and SMG are independent of inoculum size, cell density, and drug concentration.
“FoG and SMG were independent of inoculum size, cell density or drug concentration”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [194] Rosenberg, 2018, Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia, Nat Commun source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionAlteration of sphingolipid synthesis mediated through FEN1 and FEN12 deletion results in fluconazole resistance.
“alteration of sphingolipid synthesis mediated through FEN1 and FEN12 deletion results in fluconazole resistance”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [195] Gao, 2018, Candida albicans gains azole resistance by altering sphingolipid composition, Nat Commun source
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionFoG and SMG do not correlate with MIC and measure a drug response distinct from MIC.
“Neither parameter correlated with MIC and instead measured a drug response distinct from MIC.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [194] Rosenberg, 2018, Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia, Nat Commun source
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionSecreted extracellular matrix acts as a physical barrier to drug penetration and contributes to structural integrity of biofilm.
“Biofilm drug resistance may also be attributed to the secreted extracellular matrix, which acts as a physical barrier to drug penetration and thereby directly contributes to the structural integrity of the biofilm.”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [175] Al-Fattani, 2006, Biofilm matrix of Candida albicans and Candida tropicalis: chemical composition and role in drug resistance, J Med Microbiol source
Not checked in the free run.
- cites [176] Baillie, 2000, Matrix polymers of Candida biofilms and their possible role in biofilm resistance to antifungal agents, J Antimicrob Chemother source
Not checked in the free run.
- cites [177] Nett, 2007, Putative role of β-1,3 glucans in Candida albicans biofilm resistance, Antimicrob Agents Chemother source
Not checked in the free run.
- cites [178] Nett, 2010, Genetic basis of Candida biofilm resistance due to drug-sequestering matrix glucan, J Infect Dis source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ IntroductionPresence and degree of trailing growth is affected by temperature and pH and can affect MIC interpretation depending on time of reading (24 h versus 48 h).
“The presence and degree of trailing growth has been known to be affected by different parameters such as temperature and pH and can affect the MIC interpretation depending on the time of reading (24 h versus 48 h).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [186] Arthington-Skaggs, 2002, Comparison of visual and spectrophotometric methods of broth microdilution MIC end point determination and evaluation of a sterol quantitation method for in vitro susceptibility testing of fluconazole and itraconazole against trailing and nontrailing Candida isolates, Antimicrob Agents Chemother source
Not checked in the free run.
- cites [189] Luna-Tapia, 2018, Loss of C-5 sterol desaturase activity in Candida albicans: azole resistance or merely trailing growth?, Antimicrob Agents Chemother source
Not checked in the free run.
- cites [190] Marr, 1999, The trailing end point phenotype in antifungal susceptibility testing is pH dependent, Antimicrob Agents Chemother source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ IntroductionThere is a report of mutations in ERG5 conferring azole resistance in C. albicans, but it is isolated.
“there is a report of mutations in other ergosterol biosynthesis genes, such as ERG5, conferring azole resistance in C. albicans, this report is isolated.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [129] Martel, 2010, A clinical isolate of Candida albicans with mutations in ERG11 (encoding sterol 14α-demethylase) and ERG5 (encoding C22 desaturase) is cross resistant to azoles and amphotericin B, Antimicrob Agents Chemother source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionC. albicans isolates exhibiting trailing growth respond to azole treatment similarly to susceptible isolates in murine models and in a small sample of HIV-infected patients with recurrent oropharyngeal candidiasis.
“Past literature suggests that the C. albicans isolates exhibiting trailing growth phenomena respond to azole treatment similarly to susceptible isolates in murine models and in a small sample of HIV-infected patients with recurrent oropharyngeal candidiasis.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [191] Revankar, 1998, Interpretation of trailing endpoints in antifungal susceptibility testing by the National Committee for Clinical Laboratory Standards method, J Clin Microbiol source
Not checked in the free run.
- cites [192] Rex, 1998, Optimizing the correlation between results of testing in vitro and therapeutic outcome in vivo for fluconazole by testing critical isolates in a murine model of invasive candidiasis, Antimicrob Agents Chemother source
Not checked in the free run.
- cites [193] Arthington-Skaggs, 2000, Quantitation of Candida albicans ergosterol content improves the correlation between in vitro antifungal susceptibility test results and in vivo outcome after fluconazole treatment in a murine model of invasive candidiasis, Antimicrob Agents Chemother source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionThese sphingolipid composition changes are similar to those observed in WT cells treated with fluconazole.
“these composition changes are similar to what is observed in WT cells treated with fluconazole.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [195] Gao, 2018, Candida albicans gains azole resistance by altering sphingolipid composition, Nat Commun source
Not checked in the free run.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Among pathogenic fungi, the most commonly reported mechanism of resistance to triazoles is acquisition of mutations in the gene encoding sterol-demethylase.
“Among pathogenic fungi, the most commonly reported mechanism of resistance to the triazole class of antifungals is the acquisition of mutations in the gene encoding sterol-demethylase, the enzyme which these agents directly interact with and inhibit (1–3).”
From Delineation of the Direct Contribution of Candida auris <i>ERG11</i> Mutations to Clinical Triazole Resistance (2021) · cites this paper as [2]
Multiple mutations encoding amino acid substitutions in the middle homology region of CaTAC1 have previously been reported to be associated with fluconazole resistance.
“multiple mutations encoding amino acid substitutions in the MHR of CaTAC1 have previously been reported to be associated with fluconazole resistance (25).”
From Mutations in <i>TAC1B</i> : a Novel Genetic Determinant of Clinical Fluconazole Resistance in Candida auris (2020) · cites this paper as [25]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Gene overrepresentation is said to decrease rather than increase drug resistance
MinorThe text says chromosomal changes that overrepresent azole-resistance genes decrease drug resistance, but elsewhere says isochromosome formation confers azole resistance. The direction of the stated effect is contradictory.
“Overrepresentation of efflux pumps, ERG11 or ZCF genes involved in azole resistance as a result of chromosomal non-disjunctions, trisomy or isochromosome formation is very likely to contribute to decreased drug resistance in these cells.”
“Studies using comparative genome hybridization in various C. albicans laboratory strains observed aneuploidies mainly on chromosomes 1, 2 and 5, and it was later shown that some genomic changes such as isochromosome formation confer azole resistance in C. albicans.”
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Rybak, J. M., Muñoz, J. F., Barker, K. S., Parker, J. E., Esquivel, B. D., Berkow, E. L., Lockhart, S. R., Gade, L., Palmer, G. E., White, T. C., et al. (2020) · mBio · doi:10.1128/mbio.00365-20 · Cited by 202 · see citing works
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de Oliveira Neto, A. S., Souza, I. L. A., Amorim, M. E. S., de Freitas Souza, T., Rocha, V. N., do Couto, R. O., Fabri, R. L., & de Freitas Araújo, M. G. (2021) · Medical Mycology · doi:10.1093/mmy/myaa071 · Cited by 22 · see citing works
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Self-citation
- Authors
- Nishimoto, A. T., Sharma, C., & Rogers, P. D.
- Affiliations
- University of Tennessee Health Science Center (US)
- Corresponding author
- Nishimoto, Andrew T
- Rogers, P David
- Venue
- Journal of Antimicrobial Chemotherapy
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-10-11
- Volume
- 75
- Issue
- 2
- Pages
- 257-270
- ISSN
- 0305-7453 (ISSN-L)
- 1460-2091
- PMC
- PMC8204710
- OpenAlex
- W2979391377
- Semantic Scholar
- 34264519b99acfa69691210dccb16f1714422672
- Cited by
- 102
- References
- 201
- Citations by year
- 2026: 14 · 2025: 16 · 2024: 11 · 2023: 19 · 2022: 17 · 2021: 11 · 2020: 14
- FWCI
- 1.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Journal of Antimicrobial Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- NIH
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- Candida albicans, azole resistance, candidiasis, efflux pumps, ERG11, sterol biosynthesis, zinc cluster transcription factors, antifungal resistance mechanisms
- MeSH terms
- Antifungal Agents, Azoles, Candida albicans, Candidiasis, Fungal Proteins, Humans, Microbial Sensitivity Tests, Transcription Factors, Drug Resistance, Fungal
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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