Functional information from clinically-derived drug resistant forms of the Candida glabrata Pdr1 transcription factor

Simonicova, Lucia; Moye‐Rowley, W. Scott

doi:10.1371/journal.pgen.1009005

Cited by 36 publications

(43 citation statements)

References 32 publications

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“…S1, further confirming the resistance of the strains to fluconazole relative to the upc2A∆. As discussed above, the most common mechanism of fluconazole resistance is Pdr1 gain-of-function mutations that lead to increased expression of Cdr1, a putative fluconazole efflux pump (7,8). To determine if any of the 11 large colony isolates had increased Cdr1 expression, we analyzed the protein levels of Cdr1 protein in the suppressor strains by western blot (Fig.…”

Section: Experimental Laboratory Evolution Generates Suppressors Of Upc2a∆ Fluconazole Hypersusceptibilitysupporting

confidence: 54%

Loss-of-function ROX1 mutations suppress the fluconazole susceptibility of upc2AΔ mutation in Candida glabrata, implicating additional positive regulators of ergosterol biosynthesis

Ollinger

Daniel

et al. 2021

Preprint

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Two of the major classes of antifungal drugs in clinical use target ergosterol biosynthesis. Despite its importance, our understanding of the transcriptional regulation of ergosterol biosynthesis genes in pathogenic fungi is essentially limited to the role of hypoxia and sterol-stress induced transcription factors such as Upc2 and Upc2A as well as homologs of Sterol Response Element Binding (SREB) factors. To identify additional regulators of ergosterol biosynthesis in Candida glabrata, an important human fungal pathogen with reduced susceptibility to ergosterol biosynthesis inhibitors relative to other Candida spp., we used a serial passaging strategy to isolate suppressors of the fluconazole hypersusceptibility of a upc2AΔ deletion mutant. This led to the identification of loss of function mutants in two genes: ROX1, the homolog of a hypoxia gene transcriptional suppressor in Saccharomyces cerevisiae, and CST6, a transcription factor that is involved in the regulation of carbon dioxide response in C. glabrata. Here, we describe a detailed analysis of the genetic interaction of ROX1 and UPC2A. In the presence of fluconazole, loss of Rox1 function restores ERG11 expression to the upc2AΔ mutant and inhibits the expression of ERG3 and ERG6, leading to increased levels or ergosterol and decreased levels of the toxic sterol, 14α methyl-ergosta-8,24(28)-dien-3β, 6α-diol, relative to upc2AΔ. Our observations establish that Rox1 is a negative regulator of ERG gene biosynthesis and indicate that a least one additional positive transcriptional regulator of ERG gene biosynthesis must be present in C. glabrata.

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Section: Experimental Laboratory Evolution Generates Suppressors Of Upc2a∆ Fluconazole Hypersusceptibilitysupporting

confidence: 54%

Loss-of-function ROX1 mutations suppress the fluconazole susceptibility of upc2AΔ mutation in Candida glabrata, implicating additional positive regulators of ergosterol biosynthesis

Ollinger

Daniel

et al. 2021

Preprint

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“…Various reports have found that antifungal-resistant C. glabrata strains have mutations associated with the Pdr1 transcription factor and the overexpression of the ABC-type efflux pumps (ATP-Binding Cassette), mainly CDR1 and CDR2 ( Candida Drug Resistance) [ 8 , 118 , 119 , 120 ]. Such pumps can translocate small molecules to the outside of the cell and are regulated by the TAC1 transcription factor [ 121 , 122 ].…”

Section: Antifungal Resistance Of the C Glabrata Complexmentioning

confidence: 99%

“…Several mutations have been identified in the PDR1 zinc-cluster-containing transcription factor in the C. glabrata complex that favor the overexpression of the CDR1 , CDR2 , SNQ2, and PDH1 transporters, which are known to carry multiple drugs [ 117 , 118 , 119 , 120 , 123 ]. For example, Hou et al observed that 14 C. glabrata isolated strains with polymorphisms in PDR1 showed increased resistance to fluconazole (MIC ≥ 64 μg/mL) [ 124 ].…”

Section: Antifungal Resistance Of the C Glabrata Complexmentioning

confidence: 99%

Candida glabrata Antifungal Resistance and Virulence Factors, a Perfect Pathogenic Combination

Frías-De-León¹,

Hernández‐Castro

Conde-Cuevas

et al. 2021

Pharmaceutics

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In recent years, a progressive increase in the incidence of invasive fungal infections (IFIs) caused by Candida glabrata has been observed. The objective of this literature review was to study the epidemiology, drug resistance, and virulence factors associated with the C. glabrata complex. For this purpose, a systematic review (January 2001–February 2021) was conducted on the PubMed, Scielo, and Cochrane search engines with the following terms: “C. glabrata complex (C. glabrata sensu stricto, C. nivariensis, C. bracarensis)” associated with “pathogenicity” or “epidemiology” or “antibiotics resistance” or “virulence factors” with language restrictions of English and Spanish. One hundred and ninety-nine articles were found during the search. Various mechanisms of drug resistance to azoles, polyenes, and echinocandins were found for the C. glabrata complex, depending on the geographical region. Among the mechanisms found are the overexpression of drug transporters, gene mutations that alter thermotolerance, the generation of hypervirulence due to increased adhesion factors, and modifications in vital enzymes that produce cell wall proteins that prevent the activity of drugs designed for its inhibition. In addition, it was observed that the C. glabrata complex has virulence factors such as the production of proteases, phospholipases, and hemolysins, and the formation of biofilms that allows the complex to evade the host immune response and generate fungal resistance. Because of this, the C. glabrata complex possesses a perfect pathogenetic combination for the invasion of the immunocompromised host.

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“…Additionally, the reduced accumulation of Pdr1 in the presence of DM Erg11 supported the view that this mutant enzyme led to Pdr1 activation as evidenced by the lower steady-state levels of this transcription factor. Previously, we used the MET3 promoter to produce either wild-type or GOF Pdr1 proteins (28). The GOF proteins were found to be less stable than the corresponding wild-type factor.…”

Section: Increased Activation Of Pdr1 and Cdr1 Transcription Seen In Presence Of Gof Pdr1mentioning

confidence: 99%

Multiple mechanisms impact fluconazole resistance of mutant Erg11 proteins in Candida glabrata

Moye‐Rowley

2021

Preprint

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Azoles remain the most common used antifungal drugs for invasive candidiasis worldwide. They specifically inhibit the fungal lanosterol a-14 demethylase enzyme, which is commonly referred to as Erg11 in fungi. Inhibition of Erg11 ultimately leads to a reduction in ergosterol production, an essential fungal membrane sterol. Many Candida species, such as Candida albicans, develop mutations in this enzyme which reduces the azole binding affinity and results in increased azole resistance. Candida glabrata is also a pathogenic yeast that has a low intrinsic susceptibility to azole drugs and easily develops elevated resistance. These azole resistant mutations are almost exclusively found to cause hyperactivity of the Pdr1 transcription factor and rarely lie within the ERG11 gene. Here, we generated C. glabrata ERG11 mutations that were analogous to azole resistance associated mutations in C. albicans ERG11. Three different Erg11 forms (Y141H, S410F, and the corresponding double mutant (DM)) conferred azole resistance in C. glabrata with the DM Erg11 form causing the strongest phenotype. The DM Erg11 also induced cross-resistance to amphotericin B and caspofungin. The azole resistance caused by the DM allele of ERG11 imposed a fitness cost that was not observed with hyperactive PDR1 alleles. These data support the view that C. glabrata does not typically acquire ERG11 mutations owing to growth defects associated with these lesions while hyperactive PDR1 alleles have no obvious growth issues. Understanding the physiology linking ergosterol biosynthesis with Pdr1-mediated regulation of azole resistance is crucial for ensuring the continued efficacy of azole drugs against C. glabrata.

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Functional information from clinically-derived drug resistant forms of the Candida glabrata Pdr1 transcription factor

Cited by 36 publications

References 32 publications

Loss-of-function ROX1 mutations suppress the fluconazole susceptibility of upc2AΔ mutation in Candida glabrata, implicating additional positive regulators of ergosterol biosynthesis

Loss-of-function ROX1 mutations suppress the fluconazole susceptibility of upc2AΔ mutation in Candida glabrata, implicating additional positive regulators of ergosterol biosynthesis

Candida glabrata Antifungal Resistance and Virulence Factors, a Perfect Pathogenic Combination

Multiple mechanisms impact fluconazole resistance of mutant Erg11 proteins in Candida glabrata

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