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Cited by 156Evolution and Genetic DynamicsFungal and yeast genetics researchAntifungal resistance and susceptibility

Mode of Selection and Experimental Evolution of Antifungal Drug Resistance in Saccharomyces cerevisiae

Anderson, James B, Sirjusingh, Caroline, Parsons, Ainslie B, Boone, Charles, Wickens, Claire, Cowen, Leah E, Kohn, Linda M·2003·Genetics
DOI 10.1093/genetics/163.4.1287
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Abstract

We show that mode of selection, degree of dominance of mutations, and ploidy are determining factors in the evolution of resistance to the antifungal drug fluconazole in yeast. In experiment 1, yeast populations were subjected to a stepwise increase in fluconazole concentration over 400 generations. Under this regimen, two mutations in the same two chromosomal regions rose to high frequency in parallel in three replicate populations. These mutations were semidominant and additive in their effect on resistance. The first of these mutations mapped to PDR1 and resulted in the overexpression of the ABC transporter genes PDR5 and SNQ2. These mutations had an unexpected pleiotropic effect of reducing the residual ability of the wild type to reproduce at the highest concentrations of fluconazole. In experiment 2, yeast populations were subjected to a single high concentration of fluconazole. Under this regimen, a single recessive mutation appeared in each of three replicate populations. In a genome-wide screen of approximately 4700 viable deletion strains, 13 were classified as resistant to fluconazole (ERG3, ERG6, YMR102C, YMR099C, YPL056C, ERG28, OSH1, SCS2, CKA2, SML1, YBR147W, YGR283C, and YLR407W). The mutations in experiment 2 all mapped to ERG3 and resulted in the overexpression of the gene encoding the drug target ERG11, but not PDR5 and SNQ2. Diploid hybrids from experiments 1 and 2 were less fit than the parents in the presence of fluconazole. In a variation of experiment 2, haploids showed a higher frequency of resistance than diploids, suggesting that degree of dominance and ploidy are important factors in the evolution of antifungal drug resistance.

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Crossref · 10.1093/genetics/163.4.1287

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  • Little is known about how prolonged exposure to a constant drug concentration impacts evolutionary trajectories and what distinguishes selection for azole resistance from azole tolerance.

    “The impact of drug concentration on the spectrum and effect of mutations acquired during adaptation is not known for any fungal pathogen, and how the specific level of a given stress influences the distribution of beneficial mutations has been poorly explored in general.”

    From Antifungal Drug Concentration Impacts the Spectrum of Adaptive Mutations in <i>Candida albicans</i> (2023) · cites this paper as Anderson et al. 2003

  • In a similar example, three lineages from one genetic background of haploid Saccharomyces cerevisiae were exposed to increasing concentrations of fluconazole over 400 generations, starting at 16 μg/ml and increasing every 100 generations to 32, 64, and 128 μg/ml fluconazole.

    “In a similar example, three lineages from one genetic background of haploid S. cerevisiae were exposed to increasing concentrations of FLC over the span of 400 generations, starting at 16 μg/ml FLC and increasing every 100 generations to 32 μg/ml, 64 μg/ml, and 128 μg/ml FLC (Anderson et al. 2003).”

    From Antifungal Drug Concentration Impacts the Spectrum of Adaptive Mutations in <i>Candida albicans</i> (2023) · cites this paper as Anderson et al. 2003

  • Prior studies into how antifungal drugs impact the spectrum of mutations observed during adaptation primarily focused on increasing fluconazole concentrations or on short-term evolution experiments in a single concentration of fluconazole.

    “Prior studies into how antifungal drugs impact the spectrum of mutations observed during adaption primarily focused on increasing FLC concentrations or on short-term evolution experiments in a single concentration of FLC (Cowen et al. 2000; Anderson et al. 2003; Mount et al. 2018; Rybak et al. 2020; Burrack et al. 2022).”

    From Antifungal Drug Concentration Impacts the Spectrum of Adaptive Mutations in <i>Candida albicans</i> (2023) · cites this paper as Anderson et al. 2003

  • The impact of genetic and environmental factors, including fluconazole concentration, on the acquisition of drug resistance and tolerance phenotypes is not known.

    “Overall, the impact of genetic and environmental factors, including FLC concentration, on the acquisition of drug resistance and tolerance phenotypes is not known.”

    From Antifungal Drug Concentration Impacts the Spectrum of Adaptive Mutations in <i>Candida albicans</i> (2023) · cites this paper as Anderson et al. 2003

  • Several studies have shown a high consistency between results obtained in vivo and in vitro in yeasts like C. albicans and S. cerevisiae.

    “Several studies have shown a high consistency between results obtained in vivo and in vitro in yeasts like C. albicans and S. cerevisiae [147,148].”

    From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [148]

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Authors
Anderson, J. B., Sirjusingh, C., Parsons, A. B., Boone, C., Wickens, C., Cowen, L. E., & Kohn, L. M.
Affiliations
University of Toronto (CA)
Corresponding author
Anderson, James B
ORCID
Venue
Genetics
Publisher
Oxford University Press (OUP)
Published
2003-04-01
Volume
163
Issue
4
Pages
1287-1298
ISSN
  • 0016-6731 (ISSN-L)
  • 1943-2631
DOI
10.1093/genetics/163.4.1287
OpenAlex
W2143154997
Cited by
156
References
31
Citations by year
2026: 5 · 2025: 3 · 2024: 5 · 2023: 3 · 2022: 5 · 2021: 11 · 2020: 10 · 2019: 10 · 2018: 5 · 2017: 10 · 2016: 5 · 2015: 6 · 2014: 10 · 2013: 5 · 2012: 10
FWCI
4.05
Type
journal article
Language
en
Open access
closed
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Genetics (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Keywords
antifungal resistance, fluconazole resistance, Saccharomyces cerevisiae, experimental evolution, ploidy, PDR1, PDR5, ERG3, ERG11, pleiotropy
MeSH terms
Diploidy, Dose-Response Relationship, Drug, Biological Evolution, Haploidy, Saccharomyces cerevisiae, Selection, Genetic, Fluconazole, Drug Resistance, Fungal

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