New Mechanisms of Flucytosine Resistance in C. glabrata Unveiled by a Chemogenomics Analysis in S. cerevisiae
Open accessAbstract
5-Flucytosine is currently used as an antifungal drug in combination therapy, but fungal pathogens are rapidly able to develop resistance against this drug, compromising its therapeutic action. The understanding of the underlying resistance mechanisms is crucial to deal with this problem. In this work, the S. cerevisiae deletion mutant collection was screened for increased resistance to flucytosine. Through this chemogenomics analysis, 183 genes were found to confer resistance to this antifungal agent. Consistent with its known effect in DNA, RNA and protein synthesis, the most significant Gene Ontology terms over-represented in the list of 5-flucytosine resistance determinants are related to DNA repair, RNA and protein metabolism. Additional functional classes include carbohydrate and nitrogen-particularly arginine-metabolism, lipid metabolism and cell wall remodeling. Based on the results obtained for S. cerevisiae as a model system, further studies were conducted in the pathogenic yeast Candida glabrata. Arginine supplementation was found to relieve the inhibitory effect exerted by 5-flucytosine in C. glabrata. Lyticase susceptibility was found to increase within the first 30min of 5-flucytosine exposure, suggesting this antifungal drug to act as a cell wall damaging agent. Upon exponential growth resumption in the presence of 5-flucytosine, the cell wall exhibited higher resistance to lyticase, suggesting that cell wall remodeling occurs in response to 5-flucytosine. Additionally, the aquaglyceroporin encoding genes CgFPS1 and CgFPS2, from C. glabrata, were identified as determinants of 5-flucytosine resistance. CgFPS1 and CgFPS2 were found to mediate 5-flucytosine resistance, by decreasing 5-flucytosine accumulation in C. glabrata cells.
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Decreased susceptibility towards flucytosine has been associated with point mutations in FCY1, FCY2, and FUR1 genes and the deletion of FPS1 and FPS2 genes.
“Decreased susceptibility towards flucytosine has been associated with point mutations in FCY1, FCY2, and FUR1 genes and the deletion of FPS1 and FPS2 genes [36,114,115,116,117].”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [117]
Such flucytosine resistance mechanisms have been observed in C. albicans, C. lusitaniae, and C. glabrata.
“Such resistance mechanisms have been observed in C. albicans [114], C. lusitaniae [115], and C. glabrata [116,117].”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [117]
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- Authors
- Costa, C., Ponte, A., Pais, P., Santos, R., Cavalheiro, M., Yaguchi, T., Chibana, H., & Teixeira, M. C.
- Affiliations
- University of Lisbon (PT)
- Chiba University (JP)
- Corresponding author
- Teixeira, Miguel Cacho
- ORCID
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-08-12
- Volume
- 10
- Issue
- 8
- Pages
- e0135110
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4534419
- OpenAlex
- W1814010719
- Cited by
- 46
- References
- 35
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 8 · 2022: 5 · 2021: 6 · 2020: 4 · 2019: 4 · 2018: 4 · 2017: 4 · 2016: 3
- FWCI
- 2.86
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (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)
- Funders
- Drexel University
- Fundação para a Ciência e a Tecnologia (UID/BIO/04565/2013, PTDC/EBB-BIO/119356/2010)
- 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
- flucytosine resistance, Candida glabrata, chemogenomics, antifungal resistance, arginine metabolism, cell wall remodeling, aquaglyceroporins, drug accumulation, DNA repair
- MeSH terms
- Antifungal Agents, Candida, Flucytosine, Fungal Proteins, Saccharomyces cerevisiae, Genome, Fungal, Drug Resistance, Fungal, Aquaglyceroporins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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