Candida glabrata: Pathogenicity and Resistance Mechanisms for Adaptation and Survival

In the paper

“Candida glabrata has well-characterised genes, including ACE2 (CgACE2), a transcription factor that serves as a negative regulator of virulence.”

In the paper

“It accounts for approximately 15–25% of invasive clinical cases [8,11,12].”

What the sources say

• Not checked yetcites [8] Kounatidis, 2018, A Host-Pathogen Interaction Screen Identifies ada2 as a Mediator of Candida glabrata Defenses against Reactive Oxygen Species, G3 Genes Genomes Genet. source
• Not checked yetcites [11] McCarty, 2016, Invasive Candidiasis, Infect. Dis. Clin. N. Am. source
• Not checked yetcites [12] Pfaller, 2007, Epidemiology of Invasive Candidiasis: A Persistent Public Health Problem, Clin. Microbiol. Rev. source

In the paper

“It is the second most isolated Candida species associated with invasive candidiasis (IC) behind C. albicans.”

In the paper

“These adhesins facilitate C. glabrata attachment to host epithelial cells and assist in macrophage entry [25].”

What the sources say

• Not checked yetcites [25] 2018, Deletion of ADA2 Increases Antifungal Drug Susceptibility and Virulence in Candida glabrata, Antimicrob. Agents Chemother. source

In the paper

“Both mutants have enhanced virulence.”

In the paper

“Candida glabrata lacks yeast-to-hyphae switching, it grows only in the yeast form, contrary to the virulent switch of C. albicans.”

In the paper

“Invasive candidiasis due to C. glabrata causes substantial morbidity and mortality of approximately 40–60%, perhaps due to the inherent low susceptibility of C. glabrata to the most commonly used azoles [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

“Galocha et al. [13] viewed that the pathogenicity of C. glabrata appears to be independent of the morphology of the yeast as this species is incapable of hyphae formation.”

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

In the paper

“The evolved (Evo) strain is another hyper-virulent C. glabrata strain with a single nucleotide mutation in the chitin synthase gene CHS2.”

In the paper

“Candida glabrata requires iron as an essential micronutrient for its growth during infection.”

In the paper

“Arendrup and Patterson [43] argued that C. glabrata developed acquired resistance to antifungal drugs through prolonged exposure.”

What the sources say

• Not checked yetcites [43] Arendrup, 2017, Multidrug-Resistant Candida: Epidemiology, Molecular Mechanisms, and Treatment, J. Infect. Dis. source

In the paper

“Contrary to the view of Yan et al. [66] that overexpression of the transcription factor CgCrz1p enhances viability, cellular biomass, and pyruvate yields at a low pH.”

What the sources say

• Not checked yetcites [66] Yan, 2016, Crz1p Regulates pH Homeostasis in Candida glabrata by Altering Membrane Lipid Composition, Appl. Environ. Microbiol. source

In the paper

“Moreover, the findings reported the necessity of isocitrate lyase (ICL1), the glyoxylate cycle gene for acetate utilisation, ethanol, and oleic acid, and partly required for the utilisation of lactate in C. glabrata.”

In the paper

“Candida glabrata lacks hyphal formation and phagosomal extrusions to escape the phagocytic cells attack contrary to C. albicans [68,69].”

What the sources say

• Not checked yetcites [68] Yih, C.S., Than, L., and Lung, T. (2012). Candida glabrata: Niche adaptation and mechanisms of survival. Updates in Medical Microbiology, Universiti Putra Malaysia Press.
• Not checked yetcites [69] Roetzer, 2010, Autophagy supports Candida glabrata survival during phagocytosis, Cell. Microbiol. source

In the paper

“Approximately more than 140 alterations in the ERG11 target gene have been described.”

In the paper

“It is a well-known fact that both C. krusei and some C. glabrata have intrinsic resistance to fluconazole.”

In the paper

“Lactate-grown C. glabrata cells, for example, resist killing by macrophages and have developed distinct tactics for intracellular survival killing and escaping phagocytosis [41].”

What the sources say

• Not checked yetcites [41] Mota, 2015, Candida glabrata susceptibility to antifungals and phagocytosis is modulated by acetate, Front. Microbiol. source

In the paper

“Torres et al. [91] viewed that aneuploidy causes a transcriptional response that results in gene expression in chromosomes.”

What the sources say

• Not checked yetcites [91] Torres, 2007, Effects of Aneuploidy on Cellular Physiology and Cell Division in Haploid Yeast, Science source

In the paper

“Aged cells exhibit different lipid composition that leads to the emergence of azole resistance.”

In the paper

“Candida glabrata grows optimally at 37 °C and, therefore, thrives best in the human host and can grow at 42 °C under heat-stressed conditions [18,57].”

What the sources say

• Not checked yetcites [18] 2016, The birth of a deadly yeast: Tracing the evolutionary emergence of virulence traits in Candida gla-brata, FEMS Yeast Res.
• Not checked yetcites [57] Roetzer, 2008, Candida glabrata environmental stress response involves Saccharomyces cerevisiae Msn2/4 orthologous transcription factors, Mol. Microbiol. source

In the paper

“Moreover, Jensen et al. [82] supported the view that prolonged administration of antifungal drugs for treatment and prevention is the primary cause of the emergence of resistant strains.”

What the sources say

• Not checked yetcites [82] Jensen, 2016, Posttreatment Antifungal Resistance among Colonizing Candida Isolates in Candidemia Patients: Results from a Systematic Multicenter Study, Antimicrob. Agents Chemother. source

In the paper

“The former was azole sensitive, while the latter was azole-resistant.”

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

“Candida glabrata possesses numerous resistance mechanisms to fluconazole, including fluctuation of gene regulation, genetic mutations, and cross-resistance among azole derivatives [86].”

What the sources say

• Not checked yetcites [86] Gohar, 2017, Expression patterns of ABC transporter genes in fluconazole-resistant Candida glabrata, Mycopathologia source

In the paper

“Considering the role of dimorphism as a factor for pathogenicity in some Candida species, C. glabrata is exceptional; it does not germinate into hyphae yet is virulent [73].”

What the sources say

• Not checked yetcites [73] Benito, 2017, Yeast community in traditional Portuguese Serpa cheese by culture-dependent and -independent DNA approaches, Int. J. Food Microbiol. source

In the paper

“The in vivo study by Bhattacharya et al. [76] viewed that the neutrophils cells in the host selectively kill younger cells, leaving the old yeast cells to accumulate.”

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

“Mutations in ERG11 and PDR1 can mediate azole resistance; daughter cells will inherit the mutations and persist [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

“Thus, C. glabrata shows a unique immune system evasion mechanism and survives after cellular engulfment despite the antifungal presence.”

In the paper

“According to the findings of Srivastava et al. [50] that the high-affinity reductive iron uptake system is necessary for metabolism in the presence of alternate carbon sources and for growth under both in vitro and in vivo iron-limiting conditions.”

What the sources say

• Not checked yetcites [50] Srivastava, 2014, A systematic analysis reveals an essential role for high-affinity iron uptake system, haemolysin and CFEM domain-containing protein in iron homoeostasis and virulence in Candida glabrata, Biochem. J. source

In the paper

“More specifically, the free nitrogen atom of the azole ring binds an iron atom within the enzyme haem group. Thus, it prevents oxygen activation and causes demethylation of lanosterol that inhibits the ergosterol biosynthesis process.”

In the paper

“Duplications increase the level of drug resistance, as ABC transporters are implicated in pleiotropic drug resistance.”

In the paper

“However, Sasso et al. [103] reported increasing isolation of echinocandin C. glabrata-resistant strains, significantly associated with FKS1 and FKS2 gene mutations.”

What the sources say

• 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

“It is used in the pharmacotherapy of life-threatening fungal infections [107].”

What the sources say

• Not checked yetcites [107] Rodrigues, 2016, Candida glabrata’s recurrent infections: Biofilm formation during Amphotericin B treatment, Lett. Appl. Microbiol. source

In the paper

“Echinocandins are recommended as first-line therapy for non-neutropenic patients associated with C. albicans and C. glabrata in suspected severe IC conditions [100].”

What the sources say

• Not checked yetcites [100] Wanjare, 2016, Caspofungin MIC Distribution amongst Commonly Isolated Candida Species in a Tertiary Care Centre—An Indian Experience, J. Clin. Diagn. Res.

In the paper

“All isolates were highly susceptible to anidulafungin except C. glabrata with 10% resistance.”

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

“Amphotericin B (AmB) is a fungicidal polyene and has shown promising activity against many Candida species.”

What the sources say

• Not checked yetcites [107] Rodrigues, 2016, Candida glabrata’s recurrent infections: Biofilm formation during Amphotericin B treatment, Lett. Appl. Microbiol. source

In the paper

“Echinocandins exist according to the international guidelines in three available types (caspofungin, anidulafungin, and micafungin).”

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 findings attributed lower resistance of C. glabrata with biofilms against amphotericin and not about the low biofilm content of the isolates tested.”

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

“They differ based on the route of metabolism, half-life, and safety [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

“This is because both human and fungal cells’ biomembranes are the primary targets of the AmB. Thus, impairing the physiological processes that take place in the membranes, particularly adenocarcinoma cells [108].”

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

“The prevalence of echinocandin resistance among Candida strains remains low, with around 4% observed in C. glabrata and less than 1% in C. albicans [103].”

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

  “Shields et al. [105] reported low echinocandin resistance, around 4% for C. glabrata and less than 1% for C. albicans.”

What the sources say

• Not checked yetcites [103] Sasso, 2017, Rapid emergence of FKS mutations in Candida glabrata isolates in a peritoneal candidiasis, Med. Mycol. Case Rep. source
• Not checked yetcites [105] Shields, 2016, Rate of FKS Mutations among Consecutive Candida Isolates Causing Bloodstream Infection, Antimicrob. Agents Chemother. source

In the paper

“Intrinsic resistance to echinocandins is rare and primarily only observed in Candida parapsilosis [103].”

What the sources say

• 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

“Echinocandins were launched in the early 2000s and became the first-line treatment following the emergence of C. glabrata with reduced susceptibility to fluconazole Colombo et al. [101].”

What the sources say

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

In the paper

“According to the clinical laboratory standard institute (CLSI) M27-A2, the interpretative breakpoints for fluconazole for in vitro testing of Candida species using broth microdilution method is ≤8 µg mL−1 for susceptible (S), 16–32 µg ml−1 for susceptible-dose dependent (S-DD), and ≥64 µg mL−1 for resistant (R) [99].”

What the sources say

• Not checked yetcites [99] Wayne, P. (2017). Clinical and laboratory standards institute: Reference method for broth dilution antifungal susceptibility testing of yeasts. Approved Standard, Clinical and Laboratory Standards Institute.

In the paper

“These findings agreed with the view of Larkin et al. [98] that newer azoles, such as posaconazole and voriconazole, replaced fluconazole in prophylaxis routines and have raised similar concerns about resistance and drug-drug interactions as observed in azoles.”

What the sources say

• Not checked yetcites [98] Larkin, 2018, Biofilms and beyond: Expanding echinocandin utility, J. Antimicrob. Chemother. source

In the paper

“One major setback of echinocandins oral administration is the inadequate bioavailability, and therefore, it is often given intravenously [104].”

What the sources say

• Not checked yetcites [104] Walker, 2009, Methods in Molecular Biology. TM Series Editor, Life Sci.

In the paper

“The study of Aslani et al. [111] reported that 39% of yeast strains from cancer patients showed higher MIC values to AmB, with MIC90 values of 4 μg/mL.”

What the sources say

• Not checked yetcites [111] Shokohi, 2018, Candida infanticola and Candida spencermartinsiae yeasts: Possible emerging species in cancer patients, Microb. Pathog. source

In the paper

“Moreover, Candida species possess many virulence factors, including secretion of hydrolytic enzymes host cell wall adherence, and biofilm formation.”

In the paper

“Candida glabrata cells become engulfed in the macrophages. They quickly adopt other mechanisms of survival by undergoing massive division and release upon rupture.”

In the paper

“This underlines the capacity of Candida cells to rapidly adjust to external aggressions. Thus, this suggests why patients undergoing AmB therapy may still manifest resilient Candida infections.”

What the sources say

• Not checked yetcites [107] Rodrigues, 2016, Candida glabrata’s recurrent infections: Biofilm formation during Amphotericin B treatment, Lett. Appl. Microbiol. source

In the paper

“The alteration of host interaction factors facilitates opportunistic harmless commensal Candida species to become potentially life-threatening human pathogens.”

In the paper

“In contrast, Rodrigues et al. [107] viewed that C. glabrata can produce biofilms in the presence of AmB therapeutic concentrations due to the high concentrations of carbohydrate and β-1,3 glucan on the biofilm matrices.”

What the sources say

• Not checked yetcites [107] Rodrigues, 2016, Candida glabrata’s recurrent infections: Biofilm formation during Amphotericin B treatment, Lett. Appl. Microbiol. source

In the paper

“Moreover, acquired and intrinsic resistance to fluconazole and rapid resistance development to a few available antifungal drugs are of significant clinical concern.”