Journal article
Azole-Resistant Alleles of ERG11 in Candida glabrata Trigger Activation of the Pdr1 and Upc2A Transcription Factors
Antimicrobial agents and chemotherapy, Vol.66(3), p.e0209821
03/15/2022
DOI: 10.1128/aac.02098-21
PMCID: PMC8923186
PMID: 35007132
Abstract
Azoles, the most commonly used antifungal drugs, specifically inhibit the fungal lanosterol α-14 demethylase enzyme, which is referred to as Erg11. Inhibition of Erg11 ultimately leads to a reduction in ergosterol production, an essential fungal membrane sterol.
ABSTRACT
Azoles, the most commonly used antifungal drugs, specifically inhibit the fungal lanosterol α-14 demethylase enzyme, which is referred to as Erg11. 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 resistance.
Candida glabrata
is also a pathogenic yeast that has low intrinsic susceptibility to azole drugs and easily develops elevated resistance. In
C. glabrata
, these azole resistant mutations typically 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 alleles from
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. Resistance caused by the DM allele of
ERG11
imposed a fitness cost that was not observed with hyperactive
PDR1
alleles. Crucially, the presence of the DM
ERG11
allele was sufficient to activate the Pdr1 transcription factor in the absence of azole drugs. Our data indicate that azole resistance linked to changes in
ERG11
activity can involve cellular effects beyond an alteration in this key azole target enzyme. 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
.
Details
- Title: Subtitle
- Azole-Resistant Alleles of ERG11 in Candida glabrata Trigger Activation of the Pdr1 and Upc2A Transcription Factors
- Creators
- Bao Gia Vu - University of IowaW. Scott Moye-Rowley - Roy J. and Lucille A. Carver College of Medicine
- Resource Type
- Journal article
- Publication Details
- Antimicrobial agents and chemotherapy, Vol.66(3), p.e0209821
- DOI
- 10.1128/aac.02098-21
- PMID
- 35007132
- PMCID
- PMC8923186
- ISSN
- 0066-4804
- eISSN
- 1098-6596
- Grant note
- DOI: 10.13039/100000060, name: HHS | NIH | National Institute of Allergy and Infectious Diseases, award: AI152494
- Language
- English
- Date published
- 03/15/2022
- Academic Unit
- Molecular Physiology and Biophysics; Internal Medicine
- Record Identifier
- 9984302995602771
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