Attenuating the emergence of anti-fungal drug resistance by harnessing synthetic lethal interactions in a model organism
Open accessAbstract
Drug resistance is a rapidly emerging concern, thus prompting the development of novel therapeutics or combinatorial therapy.Currently, combinatorial therapy targets are based on knowledge of drug mode of action and/or resistance mechanisms, constraining the number of target proteins.Unbiased genome-wide screens could reveal novel genetic components within interaction networks as potential targets in combination therapies.Testing this, in the context of antimicrobial resistance, we implemented an unbiased genome-wide screen, performed in Saccharomyces cerevisiae expressing a Candida glabrata PDR1+ gain-of-function allele.Gain-of-function mutations in this gene are the principal mediators of fluconazole resistance in this human fungal pathogen.Eighteen synthetically lethal S. cerevisiae genetic mutants were identified in cells expressing C. glabrata PDR1+.One mutant, lacking the histone acetyltransferase Gcn5, was investigated further.Deletion or drug-mediated inhibition of Gcn5 caused a lethal phenotype in C. glabrata cells expressing PDR1 + alleles.Moreover, deletion or drug-mediated inactivation of Gcn5, inhibited the emergence of fluconazole-resistant C. glabrata isolates in evolution experiments.Thus, taken together, the data generated in this study provides proof of concept that synthetically lethal genetic screens can identify novel candidate proteins that when therapeutically targeted could allow effective treatment of drug-resistant infections. Author summaryLife threatening infections are an increasing reality.Multi-drug resistant bacteria e.g.MRSA are present in nearly all hospitals, and community acquired TB is often recalcitrant to treatment.Less well known, but causing four to five times more deaths in the UK than MRSA, are fungi in the genus Candida.These are commonly associated with mucosal infections such as "thrush", but are responsible for > 400,000 life-threatening infections worldwide every year, especially in the immunosuppressed patient population.One of the principle pathogens is Candida glabrata.This fungus grows as a single celled yeast, and alarmingly is highly resistant to both host innate defences and many clinically used antifungal drugs.Even with the best possible medical care, infections with this yeast cause
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Lysine acetyltransferases such as Gcn5 mediate antifungal tolerance and resistance in Candida species.
“Lysine acetyltransferases, such as Gcn5, also mediate antifungal tolerance and resistance in Candida species93–95.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [95]
Histone modifications are important not only in the maintenance of azole resistance but also in the acquisition of azole resistance.
“Notably, in C. glabrata, inhibition of Gcn5 minimized the emergence of PDR1 gain-of-function alleles in evolution experiments with fluconazole, suggesting the importance of histone modifications not only in the maintenance of azole resistance but also in the acquisition of azole resistance95.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [95]
In C. glabrata, inhibition of Gcn5 minimized the emergence of PDR1 gain-of-function alleles in evolution experiments with fluconazole.
“Notably, in C. glabrata, inhibition of Gcn5 minimized the emergence of PDR1 gain-of-function alleles in evolution experiments with fluconazole, suggesting the importance of histone modifications not only in the maintenance of azole resistance but also in the acquisition of azole resistance95.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [95]
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Self-citationAntifungal resistance: from classical mechanisms to the expanding role of acetyltransferases
Werneck, S. M. C., Gouveia‐Eufrásio, L., de Freitas, G. J. C., de Carvalho, D. S., César, I. C., Rossato, L. L., Bastos, R. W., Peres, N. T. A., & Santos, D. A. (2026) · Journal of Biomedical Science · doi:10.1186/s12929-026-01273-8
- Authors
- Usher, J., & Haynes, K.
- Affiliations
- University of Exeter (GB)
- Corresponding author
- Usher, Jane
- ORCID
- Usher, Jane
- Venue
- PLOS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2019-08-19
- Volume
- 15
- Issue
- 8
- Pages
- e1008259
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC6715234
- OpenAlex
- W2969584321
- Cited by
- 27
- References
- 32
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 2 · 2023: 2 · 2022: 4 · 2021: 2 · 2020: 10
- FWCI
- 3.07
- Type
- journal article
- Language
- en
- Update notices
- new_version (2019-08-29)
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Open Research Exeter (University of Exeter) (submittedVersion, cc-by)
- Funders
- U.S. Department of Defense
- Medical Research Council (MR/N006364/1)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- antifungal resistance, synthetic lethality, Candida glabrata, fluconazole resistance, PDR1, GCN5, histone acetyltransferase, Saccharomyces cerevisiae, genome-wide screen, combination therapy, drug resistance evolution
- MeSH terms
- Synthetic Lethal Mutations, Gain of Function Mutation, p300-CBP-Associated Factor, Antifungal Agents, Candidiasis, Humans, Microbial Sensitivity Tests, Saccharomyces cerevisiae, Fluconazole, Gene Expression Regulation, Fungal, Drug Resistance, Fungal, Saccharomyces cerevisiae Proteins, Candida glabrata, Histone Acetyltransferases
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