Candida glabrata: Pathogenicity and Resistance Mechanisms for Adaptation and Survival

In the paper

“In contrast, biofilms of C. glabrata and C. tropicalis do not possess such persister cells [13,43].”

What the sources say

• Not checked yetcites [13] Galocha, M., Pais, P., Cavalheiro, M., Pereira, D., Viana, R., and Teixeira, M.C. (2019). Divergent approaches to virulence in C. Albicans and C. Glabrata: Two sides of the same coin. Int. J. Mol. Sci., 20. source
• Not checked yetcites [43] Arendrup, 2017, Multidrug-Resistant Candida: Epidemiology, Molecular Mechanisms, and Treatment, J. Infect. Dis. source

In the paper

“Recent evidence indicates that most IC caused by C. glabrata is associated with biofilm growth [42].”

What the sources say

• Not checked yetcites [42] Sardi, 2013, Candida species: Current epidemiology, pathogenicity, biofilm formation, natural antifungal products and new therapeutic options, J. Med. Microbiol. source

In the paper

“Fungal biofilms show properties different from planktonic (free-living) populations, including a higher antifungal resistance level [39].”

What the sources say

• Not checked yetcites [39] Pierce, 2008, A simple and reproducible 96-well plate-based method for the formation of fungal biofilms and its application to antifungal susceptibility testing, Nat. Protoc. source

In the paper

“Al-Dhaheri and Douglas [46] found that the presence of persister cells in biofilms is mainly responsible for biofilm resistance.”

What the sources say

• Not checked yetcites [46] Douglas, 2008, Absence of Amphotericin B-Tolerant Persister Cells in Biofilms of Some Candida Species, Antimicrob. Agents Chemother. source

In the paper

“C. glabrata is exceptional from this rule because the cell wall is associated with serine protease, Cwp1 (ORF: CBS138)—a gelatinolytic enzyme [24].”

What the sources say

• Not checked yetcites [24] Bochenska, 2018, Extracellular proteinases of Candida species pathogenic yeasts, Mol. Oral Microbiol. source

In the paper

“A significant virulence factor of C. glabrata is its ability to adhere firmly to many different substrates [3].”

What the sources say

• Not checked yetcites [3] Timmermans, B., De Las Peñas, A., Castaño, I., and Van Dijck, P. (2018). Adhesins in Candida glabrata. J. Fungi, 4. source

In the paper

“All these frameworks are operational in C. glabrata except for the receptor-interceded haem uptake [9].”

What the sources say

• Not checked yetcites [9] Kumar, K., Askari, F., Sahu, M.S., and Kaur, R. (2019). Candida glabrata: A Lot More Than Meets the Eye. Microorganisms, 7. source

In the paper

“Thus, it is an essential pathogenic mechanism for its survival [40] (Figure 2).”

What the sources say

• Not checked yetcites [40] Santos, 2017, Candida auris: Emergence and Epidemiology of a Highly Pathogenic Yeast, Clin. Biomed. Res. source

In the paper

“Candida glabrata does not possess normal Sap genes in its genome [32].”

What the sources say

• Not checked yetcites [32] Ramos, 2016, First description of Candida nivariensis in Brazil: Antifungal susceptibility profile and potential virulence attributes, Mem. Inst. Oswaldo Cruz source

In the paper

“Chitin is essential for fungal biological functions, including cell division, septa formation, hyphal growth, and virulence [47].”

What the sources say

• Not checked yetcites [47] Charlet, 2018, Remodeling of the Candida glabrata cell wall in the gastrointestinal tract affects the gut microbiota and the immune response, Sci. Rep. source

In the paper

“However, C. glabrata produces sparse biofilm (less weight) with yeast cells.”

In the paper

“Both C. albicans and C. glabrata can form biofilms on abiotic substrates, especially medical devices including catheters and implanted materials [26,27].”

What the sources say

• Not checked yetcites [26] Kawai, 2015, In vitro efficacy of liposomal amphotericin B, micafungin and fluconazole against non-albicans Candida species biofilms, J. Infect. Chemother. source
• Not checked yetcites [27] Brunke, 2013, Two unlike cousins: Candida albicans and C. glabrata infection strategies, Cell Microbiol. source

In the paper

“Candida glabrata secretes hydrolytic enzymes (e.g., phospholipases, proteases, and haemolysins) to destroy host tissues [19].”

What the sources say

• Not checked yetcites [19] Moreira, 2015, Candida bracarensis: Evaluation of Virulence Factors and its Tolerance to Amphotericin B and Fluconazole, Mycopathologia source

In the paper

“Candida glabrata biofilms show antifungal resistance characterised by a compact, dense structure of yeast cells.”

In the paper

“High chitin content restricts the penetration of the drug through the cell wall [51].”

What the sources say

• Not checked yetcites [51] Perlin, 2014, Echinocandin resistance, susceptibility testing and prophylaxis: Implications for patient management, Drugs source

In the paper

“Candida glabrata as occur in S. cerevisiae, C. albicans, and C. neoformans show a replicative ageing, a process where original mother cells progressively age, producing asymmetric mitotic divisions resulting in phenotypically distinct daughter cells [16].”

What the sources say

• Not checked yetcites [16] Kaur, 2005, A yeast by any other name: Candida glabrata and its interaction with the host, Curr. Opin. Microbiol. source

In the paper

“According to the findings of Chew et al. [63], the growth of C. glabrata in the presence of acetate, lactate, ethanol, or oleate reduces the growth in both the planktonic and biofilm states.”

What the sources say

• Not checked yetcites [63] Chew, S.Y., Ho, K.L., Cheah, Y.K., Sandai, D., Brown, A.J., and Than, L.T.L. (2019). Physiologically Relevant Alternative Carbon Sources Modulate Biofilm Formation, Cell Wall Architecture, and the Stress and Antifungal Resistance of Candida glabrata. Int. J. Mol. Sci., 20. source

In the paper

“Candida glabrata can shift from a commensal to pathogenic state due to the pressure of neutrophils.”

In the paper

“Upon testing, BPY41 showed mitochondrial dysfunction compared to BPY40.”

What the sources say

• Not checked yetcites [93] Ferrari, 2011, Loss of mitochondrial functions associated with azole resistance in Candida glabrata results in enhanced virulence in mice, Antimicrob. Agents Chemother. source

In the paper

“Furthermore, the upregulation of Trx1p as a stress-response protein exerts defences to C. glabrata against oxidative stress [72].”

What the sources say

• Not checked yetcites [72] Wang, 2010, Proteomics of drug resistance in Candida glabrata biofilms, Proteomics source

In the paper

“The mechanism of action of azole is to target the cytochrome P450 enzyme sterol 14α-demethylase. The enzyme converts lanosterol to ergosterol as an essential structural component of the fungal cell membrane [87].”

What the sources say

• Not checked yetcites [87] Perlin, 2017, The global problem of antifungal resistance: Prevalence, mechanisms, and management, Lancet Infect. Dis. source

In the paper

“The old cells only emerge because of neutrophil pressure in the environment that favour the killing of young fungal cells and the promotion of the persistence of old cells [75].”

What the sources say

• Not checked yetcites [75] Bhattacharya, S., Bouklas, T., and Fries, B.C. (2020). Replicative Aging in Pathogenic Fungi. J. Fungi, 7. source

In the paper

“Aneuploidy gain of small chromosome segment on the left arm of chromosome F that encodes ABC transporter AUS1 and PDH1 is also observed in C. glabrata-resistant isolates [90].”

What the sources say

• Not checked yetcites [90] Blume, 2009, Formation of new chromosomes as a virulence mechanism in yeast Candida glabrata, Proc. Natl. Acad. Sci. USA source

In the paper

“A study conducted on the virulence of C. glabrata on the Galleria mellonella model indicated that G. mellonella only became susceptible to infection at 37 °C.”

In the paper

“According to Poláková et al. [90], the genetic instability results in segmental duplications, chromosomal rearrangements, and extra chromosomes occurring in C. glabrata at high frequency.”

What the sources say

• Not checked yetcites [90] Blume, 2009, Formation of new chromosomes as a virulence mechanism in yeast Candida glabrata, Proc. Natl. Acad. Sci. USA source

In the paper

“Mitochondrial DNA deficiency is another mechanism used by C. glabrata for azole resistance through the upregulation of ATP-binding cassette (ABC) transporter genes.”

What the sources say

• Not checked yetcites [92] Tsai, 2006, Candida glabrata PDR1, a Transcriptional Regulator of a Pleiotropic Drug Resistance Network, Mediates Azole Resistance in Clinical Isolates and Petite Mutants, Antimicrob. Agents Chemother. source

In the paper

“MFS transporters facilitate enhanced fluconazole efflux particularly in ageing C. glabrata cells [76].”

What the sources say

• Not checked yetcites [76] Bhattacharya, 2018, Enhanced Efflux Pump Activity in Old Candida glabrata Cells, Antimicrob. Agents Chemother. source

In the paper

“The small chromosome F encodes an ortholog of S. cerevisiae ABC transporter PDR5 (CAGL0F02717g) known in C. glabrata as PDH1.”

What the sources say

• Not checked yetcites [90] Blume, 2009, Formation of new chromosomes as a virulence mechanism in yeast Candida glabrata, Proc. Natl. Acad. Sci. USA source

In the paper

“Candida glabrata ASG1 (CgASG1, CAGL0G08844g) deletion resulted in increased tolerance to salt stress [58].”

What the sources say

• Not checked yetcites [58] Wu, 2015, Transcription factors Asg1p and Hal9p regulate pH homeostasis in Candida glabrata, Front. Microbiol. source

In the paper

“Candida glabrata has high-affinity iron uptake mechanisms as critical virulence determinants.”

In the paper

“Ferrari et al. [93] reported two C. glabrata isolates (BPY40 and BPY41) obtained from the same patient on different occasions.”

What the sources say

• Not checked yetcites [93] Ferrari, 2011, Loss of mitochondrial functions associated with azole resistance in Candida glabrata results in enhanced virulence in mice, Antimicrob. Agents Chemother. source

In the paper

“Moreover, C. glabrata shows multi-drug-resistant capacity at an alarming rate.”

In the paper

“Transcription factors Msn2 and Msn4 are crucial for resistance to various stresses in C. glabrata [58].”

What the sources say

• Not checked yetcites [58] Wu, 2015, Transcription factors Asg1p and Hal9p regulate pH homeostasis in Candida glabrata, Front. Microbiol. source

In the paper

“The low acidic environment of the vaginal tract (pH ~ 4–4.5) contributes to the increased resilience to azoles against C. glabrata and C. albicans.”

In the paper

“Chew et al. [71] revealed that the ICL1 gene helps promote the growth and prolonged survival of C. glabrata during macrophage engulfment.”

What the sources say

• Not checked yetcites [71] Chew, 2019, Glyoxylate cycle gene ICL1 is essential for the metabolic flexibility and virulence of Candida glabrata, Sci. Rep. source

In the paper

“The use of glucose as a carbon source, on the contrary, showed significant growth in both states.”

In the paper

“Several studies showed that replicative ageing in many fungal pathogens leads to significant changes that affect the fungal resistance to phagocytic clearance and antifungal therapy [75].”

What the sources say

• Not checked yetcites [75] Bhattacharya, S., Bouklas, T., and Fries, B.C. (2020). Replicative Aging in Pathogenic Fungi. J. Fungi, 7. source

In the paper

“Several genes on chromosomes (ChrEL and ChrFL) potentially mediate interactions between C. glabrata and the susceptible host.”

What the sources say

• Not checked yetcites [90] Blume, 2009, Formation of new chromosomes as a virulence mechanism in yeast Candida glabrata, Proc. Natl. Acad. Sci. USA source

In the paper

“According to the findings of Gohar et al. [86] and Farahyar et al. [88], the ATP-binding cassette transporters of drug efflux is mediated primarily by Candida glabrata sensitivity to 4 Nitroquinoline N-oxide (CgSNQ2) and Candida glabrata Candida drug resistance 1 and 2 (CgCDR1 and CgCDR2) genes.”

What the sources say

• Not checked yetcites [86] Gohar, 2017, Expression patterns of ABC transporter genes in fluconazole-resistant Candida glabrata, Mycopathologia source
• Not checked yetcites [88] Farahyar, 2016, Expression of Efflux Pumps and Fatty Acid Activator One Genes in Azole Resistant Candida glabrata Isolated from Immunocompromised Patients, Acta Med. Iran.

In the paper

“Because of the low host cell damage, C. glabrata cells elicit a cytokine profile significantly different from that of C. albicans.”

In the paper

“For example, mutations in the MSH2 gene, encoding a DNA mismatch repair protein, occur in C. glabrata. Its effects have been found in clinical isolates to facilitate the selection of resistance to azoles, echinocandins, and polyenes in vitro [1].”

What the sources say

• Not checked yetcites [1] Pappas, 2018, Invasive candidiasis, Nat. Rev. Dis. Primers source

In the paper

“The upregulation of these transporters is associated with gain-of-function (GOF) mutations in the transcriptional regulator encoded by CgPDR1.”

What the sources say

• Not checked yetcites [92] Tsai, 2006, Candida glabrata PDR1, a Transcriptional Regulator of a Pleiotropic Drug Resistance Network, Mediates Azole Resistance in Clinical Isolates and Petite Mutants, Antimicrob. Agents Chemother. source

In the paper

“The primary factor aiding the persistence of C. glabrata is its less aggressive nature to stimulate the strong reaction of the host immune system [24].”

What the sources say

• Not checked yetcites [24] Bochenska, 2018, Extracellular proteinases of Candida species pathogenic yeasts, Mol. Oral Microbiol. source

In the paper

“Duplicated segments of ChrFL encode a transporter of the ATP-binding cassette family (CAGL0F01419g) that is very similar to S. cerevisiae AUS1.”

What the sources say

• Not checked yetcites [90] Blume, 2009, Formation of new chromosomes as a virulence mechanism in yeast Candida glabrata, Proc. Natl. Acad. Sci. USA source

In the paper

“Thus, this suggested that some essential genes for C. glabrata virulence are switched on only at 37 °C [62].”

What the sources say

• Not checked yetcites [62] Ho, H.-L., and Haynes, K.F. (2015). Candida glabrata: New tools and technologies—Expanding the toolkit. FEMS Yeast Res., 15. source

In the paper

“The virulent analyses, based on mortality and fungal tissue burden in both systemic and vaginal murine infection models, suggested higher virulence of BPY41 than BPY40.”

What the sources say

• Not checked yetcites [93] Ferrari, 2011, Loss of mitochondrial functions associated with azole resistance in Candida glabrata results in enhanced virulence in mice, Antimicrob. Agents Chemother. source

In the paper

“The result also showed a 17.8% susceptibility of the standard strains to voriconazole [97].”

What the sources say

• Not checked yetcites [97] Chen, 2018, Epidemiology of fungal infections in China, Front. Med. source

In the paper

“The mechanism of action of AmB is to bind to ergosterol in the plasma membrane resulting in the leakage of cytoplasmic materials and cellular destruction [51,98].”

What the sources say

• Not checked yetcites [51] Perlin, 2014, Echinocandin resistance, susceptibility testing and prophylaxis: Implications for patient management, Drugs source
• Not checked yetcites [98] Larkin, 2018, Biofilms and beyond: Expanding echinocandin utility, J. Antimicrob. Chemother. source

In the paper

“Mutations frequently occur in FKS2 relative to FKS1 [101].”

What the sources say

• Not checked yetcites [101] Colombo, 2017, Emerging multidrug-resistant Candida species, Curr. Opin. Infect. Dis. source

In the paper

“Based on the microarray analyses, some genes responsible for cell wall remodelling were upregulated in BPY41 compared to BPY40.”

What the sources say

• Not checked yetcites [93] Ferrari, 2011, Loss of mitochondrial functions associated with azole resistance in Candida glabrata results in enhanced virulence in mice, Antimicrob. Agents Chemother. source

In the paper

“The resistance to AmB is not commonly observed in Candida species [11].”

What the sources say

• Not checked yetcites [11] McCarty, 2016, Invasive Candidiasis, Infect. Dis. Clin. N. Am. source

In the paper

“The five isolates were resistant to itraconazole.”

• Also stated in: § 3.1. Types of Drug Resistance Mechanisms · plain

  “Similarly, all the isolates were resistant to itraconazole.”

What the sources say

• Not checked yetcites [95] Song, 2015, Antifungal Susceptibility Testing with Etest for Candida Species Isolated from Patients with Oral Candidiasis, Ann. Dermatol. source

In the paper

“The emergence of resistant C. glabrata usually correlates with high azole and frequent echinocandin usage in hospitals or specific hospital wards [1].”

What the sources say

• Not checked yetcites [1] Pappas, 2018, Invasive candidiasis, Nat. Rev. Dis. Primers source

In the paper

“The resistance acquired through mutation (amino acid changes) of the critical regions in FKS1 and FKS2 genes encode β-1,3-d-glucan synthase, the potential target enzyme echinocandins [51,103].”

What the sources say

• Not checked yetcites [51] Perlin, 2014, Echinocandin resistance, susceptibility testing and prophylaxis: Implications for patient management, Drugs source
• Not checked yetcites [103] Sasso, 2017, Rapid emergence of FKS mutations in Candida glabrata isolates in a peritoneal candidiasis, Med. Mycol. Case Rep. source

In the paper

“However, Echinocandins resistance is an emerging scourge in Candida species, particularly C. glabrata [1].”

What the sources say

• Not checked yetcites [1] Pappas, 2018, Invasive candidiasis, Nat. Rev. Dis. Primers source

In the paper

“The echinocandins drugs act by inhibiting β-d-glucan synthase, an enzyme necessary for cell wall synthesis.”

What the sources say

• Not checked yetcites [1] Pappas, 2018, Invasive candidiasis, Nat. Rev. Dis. Primers source

In the paper

“The frequent prescription and usage of echinocandins result in resistance development by decreasing the targeted Candida species susceptibility [102].”

What the sources say

• Not checked yetcites [102] Yeoh, 2018, Echinocandins for management of invasive candidiasis in patients with liver disease and liver transplantation, Infect. Drug Resist. source

In the paper

“The SENTRY surveillance program between 2006 and 2010 reported 11% echinocandin and fluconazole resistance among C. glabrata (i.e., MDR) [101].”

What the sources say

• Not checked yetcites [101] Colombo, 2017, Emerging multidrug-resistant Candida species, Curr. Opin. Infect. Dis. source

In the paper

“Tay et al. [110] reported that C. glabrata isolates demonstrated similar MIC50 (0.25 μg/mL) against AmB for biofilm and planktonic cells.”

What the sources say

• Not checked yetcites [110] Tay, 2014, Occurrence and Characterization of Candida nivariensis from a Culture Collection of Candida glabrata Clinical Isolates in Malaysia, Mycopathologia source

In the paper

“In infections associated with C. glabrata or C. krusei, echinocandins offered preference over azoles.”

What the sources say

• Not checked yetcites [1] Pappas, 2018, Invasive candidiasis, Nat. Rev. Dis. Primers source

In the paper

“Mutations in two hotspot regions (HS1 and HS2) of these genes have been recognised as the primary mechanism for echinocandin resistance [1].”

What the sources say

• Not checked yetcites [1] Pappas, 2018, Invasive candidiasis, Nat. Rev. Dis. Primers source

In the paper

“These pieces of evidence suggested that virulence and resistance to azole were linked to mitochondrial dysfunction in BPY41.”

What the sources say

• Not checked yetcites [93] Ferrari, 2011, Loss of mitochondrial functions associated with azole resistance in Candida glabrata results in enhanced virulence in mice, Antimicrob. Agents Chemother. source

In the paper

“Song et al. [95] reported from South Korea that two of the five C. glabrata isolates tested were resistant to fluconazole.”

What the sources say

• Not checked yetcites [95] Song, 2015, Antifungal Susceptibility Testing with Etest for Candida Species Isolated from Patients with Oral Candidiasis, Ann. Dermatol. source

In the paper

“Based on Aslani et al. [106] findings in the study conducted in Iran on echinocandins, 27.8% of the Candida isolates showed resistance to caspofungin.”

What the sources say

• Not checked yetcites [106] Aslani, 2018, Identification of uncommon oral yeasts from cancer patients by MALDI-TOF mass spectrometry, BMC Infect. Dis. source

In the paper

“They have excellent fungicidal activity against most Candida species [1].”

What the sources say

• Not checked yetcites [1] Pappas, 2018, Invasive candidiasis, Nat. Rev. Dis. Primers source

In the paper

“A study conducted in China reported that 12.2% of C. glabrata are resistant to fluconazole.”

What the sources say

• Not checked yetcites [97] Chen, 2018, Epidemiology of fungal infections in China, Front. Med. source

In the paper

“However, the isolates were susceptible to voriconazole.”

What the sources say

• Not checked yetcites [96] Sri, 2015, Pattern of susceptibility to azoles by E test method in candidemia patients, Int. J. Res. Med. Sci.

In the paper

“Then, oxido-reductive metabolism and the stress response were also observed in the BPY41 isolate.”

What the sources say

• Not checked yetcites [93] Ferrari, 2011, Loss of mitochondrial functions associated with azole resistance in Candida glabrata results in enhanced virulence in mice, Antimicrob. Agents Chemother. source

In the paper

“Despite these therapeutic advantages, AmB has serious toxicity limitations on the human host cells.”

What the sources say

• Not checked yetcites [108] Grela, 2018, Imaging of human cells exposed to an antifungal antibiotic amphotericin B reveals the mechanisms associated with the drug toxicity and cell defence, Sci. Rep. source

In the paper

“Some studies have linked mutations in ERG2, ERG3, ERG5, ERG6, and ERG11 genes with the depletion of ergosterol as a significant cause of AmB resistance [109].”

What the sources say

• Not checked yetcites [109] Rhodes, 2018, Genomic epidemiology of the UK outbreak of the emerging human fungal pathogen Candida auris article, Emerg. Microb. Infect.

In the paper

“In a similar resistance pattern, Premamalini et al.’s [96] study conducted in Chennai, India, indicated that two (66.7%) C. glabrata isolates were resistant to fluconazole and itraconazole.”

What the sources say

• Not checked yetcites [96] Sri, 2015, Pattern of susceptibility to azoles by E test method in candidemia patients, Int. J. Res. Med. Sci.

In the paper

“For instance, Nedret Koc et al. [94] reported three C. glabrata isolates with MICs of ≥8 µg ml−1.”

What the sources say

• Not checked yetcites [94] 2000, Comparison of Etest with the broth microdilution method in susceptibility testing of yeast isolates against four antifungals, Mycoses source

In the paper

“According to the findings of Bhattacharya et al. [76], replicative ageing in C. glabrata causes higher tolerance to killings by AmB and micafungin due to the higher transcription of glucan synthase gene, FKS1.”

What the sources say

• Not checked yetcites [76] Bhattacharya, 2018, Enhanced Efflux Pump Activity in Old Candida glabrata Cells, Antimicrob. Agents Chemother. source

In the paper

“Such a ‘persister’ population was absent from the biofilms of C. glabrata.”

What the sources say

• Not checked yetcites [46] Douglas, 2008, Absence of Amphotericin B-Tolerant Persister Cells in Biofilms of Some Candida Species, Antimicrob. Agents Chemother. source

In the paper

“Candida glabrata further adopt strategies of evading the action of immune cells.”

In the paper

“According to the findings reported by Norimatsu et al. [4], the liposomal AmB (3 mg/kg/day) showed better activity than micafungin in the treatment of both C. glabrata and C. parapsilosis bloodstream infections in the case of an 80-year-old woman.”

What the sources say

• Not checked yetcites [4] Norimatsu, 2017, A case of breakthrough Candida parapsilosis fungemia during micafungin therapy for a Candida glabrata bloodstream infection, Med. Mycol. Case Rep. source

In the paper

“The factors help to increase their persistence and survival.”

In the paper

“The findings agreed with the study reported by Al-Dhaheri and Douglas [46] that ‘persister’ populations were observed in biofilms of C. albicans, C. krusei, and C. parapsilosis after exposure to amphotericin.”

What the sources say

• Not checked yetcites [46] Douglas, 2008, Absence of Amphotericin B-Tolerant Persister Cells in Biofilms of Some Candida Species, Antimicrob. Agents Chemother. source