Metabolic control of antifungal drug resistance
Abstract
Fungi have evolved an elegant repertoire of mechanisms to survive the cellular stress exerted by antifungal drugs such as azoles, which inhibit ergosterol biosynthesis inducing cell membrane stress. The evolution and maintenance of diverse resistance phenotypes is contingent upon cellular circuitry regulated by the molecular chaperone Hsp90 and its client protein calcineurin. Here, we establish a novel role for nutrients and nutrient signaling in azole resistance. The vulnerability of Saccharomyces cerevisiae azole resistance phenotypes to perturbation was contingent upon specific auxotrophies. Using strains that acquired azole resistance by Erg3 loss of function as a model for resistance that depends on cellular stress responses, we delineated genetic and environmental factors that mitigate the translation of genotype into resistance phenotype. Compromising a global regulator that couples growth and metabolism to environmental cues, Tor kinase, provides a powerful strategy to abrogate drug resistance of S. cerevisiae and Candida albicans with broad therapeutic potential.
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Loss-of-function of Erg3 confers a mode of resistance dependent upon Hsp90.
“acquired by loss-of-function of Erg3, a mode of resistance dependent upon Hsp9086.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [86]
Rapamycin blocks azole resistance acquired by loss-of-function of Erg3, a mode of resistance dependent upon Hsp90.
“In line with this, rapamycin blocks azole resistance acquired by loss-of-function of Erg3, a mode of resistance dependent upon Hsp9086.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [86]
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- Authors
- Robbins, N., Collins, C., Morhayim, J., & Cowen, L. E.
- Affiliations
- University of Toronto (CA)
- Corresponding author
- Cowen, Leah E.
- Venue
- Fungal Genetics and Biology
- Publisher
- Elsevier BV
- Published
- 2010-02
- Volume
- 47
- Issue
- 2
- Pages
- 81-93
- ISSN
- 1087-1845 (ISSN-L)
- OpenAlex
- W2018134501
- Cited by
- 40
- References
- 51
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 4 · 2019: 2 · 2018: 1 · 2017: 2 · 2016: 2 · 2015: 2 · 2014: 1 · 2013: 1 · 2012: 5
- FWCI
- 1.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Fungal Genetics and Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (MOP-86452)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- antifungal resistance, azole resistance, ergosterol biosynthesis, nutrient signaling, HSP90, calcineurin, TOR kinase, ERG3, auxotrophy, cellular stress response, Saccharomyces cerevisiae, Candida albicans
- MeSH terms
- Amino Acids, Antifungal Agents, Azoles, Culture Media, Microbial Sensitivity Tests, Mutation, Oxidoreductases, Phenotype, Saccharomyces cerevisiae, Signal Transduction, Gene Expression, Genome, Fungal, HSP90 Heat-Shock Proteins, Calcineurin, Sirolimus, Reverse Transcriptase Polymerase Chain Reaction, Drug Resistance, Fungal, Saccharomyces cerevisiae Proteins, Basic-Leucine Zipper Transcription Factors
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