Cited by 207Antifungal resistance and susceptibilityFungal and yeast genetics researchEvolution and Genetic Dynamics

Evolution of Drug Resistance in Experimental Populations of Candida albicans

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Cowen, Leah E., Sanglard, Dominique, Calabrese, David, Sirjusingh, Caroline, Anderson, James B., Kohn, Linda M.·2000·Journal of Bacteriology

Abstract

Adaptation to inhibitory concentrations of the antifungal agent fluconazole was monitored in replicated experimental populations founded from a single, drug-sensitive cell of the yeast Candida albicans and reared over 330 generations. The concentration of fluconazole was maintained at twice the MIC in six populations; no fluconazole was added to another six populations. All six replicate populations grown with fluconazole adapted to the presence of drug as indicated by an increase in MIC; none of the six populations grown without fluconazole showed any change in MIC. In all populations evolved with drug, increased fluconazole resistance was accompanied by increased resistance to ketoconazole and itraconazole; these populations contained ergosterol in their cell membranes and were amphotericin sensitive. The increase in fluconazole MIC in the six populations evolved with drug followed different trajectories, and these populations achieved different levels of resistance, with distinct overexpression patterns of four genes involved in azole resistance: the ATP-binding cassette transporter genes, CDR1 and CDR2; the gene encoding the target enzyme of the azoles in the ergosterol biosynthetic pathway, ERG11; and the major facilitator gene, MDR1. Selective sweeps in these populations were accompanied by additional genomic changes with no known relationship to drug resistance: loss of heterozygosity in two of the five marker genes assayed and alterations in DNA fingerprints and electrophoretic karyotypes. These results show that chance, in the form of mutations that confer an adaptive advantage, is a determinant in the evolution of azole drug resistance in experimental populations of C. albicans.

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Crossref · 10.1128/jb.182.6.1515-1522.2000

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  • Selective sweeps in response to drug selection are also observed in experimental populations of C. albicans during the evolution of azole resistance in vitro.

    “Selective sweeps in response to drug selection are also observed in experimental populations of C. albicans during the evolution of azole resistance in vitro [107].”
  • 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.”
  • 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.”
  • In one example, six lineages from one Candida albicans strain were maintained at increasing concentrations of fluconazole for 300-400 generations, with MIC50 quantified every 10-20 generations and drug concentration increased to twice the MIC50, to a maximum of 128 μg/ml fluconazole.

    “In one example, six lineages from one C. albicans strain were maintained at increasing concentrations of FLC for 300–400 generations, where the MIC50 was quantified every 10–20 generations and the drug concentration was increased to twice the MIC50, to a maximum concentration of 128 μg/ml FLC (Cowen et al. 2000).”
  • 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).”

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Authors
Cowen, L. E., Sanglard, D., Calabrese, D., Sirjusingh, C., Anderson, J. B., & Kohn, L. M.
Affiliations
  • University of Toronto (CA)
  • Centre Hospitalier Universitaire Vaudois (CH)
Venue
Journal of Bacteriology
Published
2000-03-15
Volume
182
Issue
6
Pages
1515-1522
ISSN
  • 0021-9193 (ISSN-L)
  • 1098-5530
OpenAlex
W1973285175
Cited by
207
References
34
Citations by year
2026: 5 · 2025: 5 · 2024: 7 · 2023: 6 · 2022: 10 · 2021: 8 · 2020: 3 · 2019: 5 · 2018: 7 · 2017: 9 · 2016: 7 · 2015: 5 · 2014: 8 · 2013: 8 · 2012: 9
FWCI
7.85
Type
journal article
Language
en
Open access
Locations
  • Journal of Bacteriology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • IRIS (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion)
Funders
  • Pfizer
  • Pfizer Canada
  • Natural Sciences and Engineering Research Council of Canada
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 › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
Keywords
Candida albicans, fluconazole resistance, experimental evolution, antifungal resistance, ketoconazole, itraconazole, CDR1, CDR2, ERG11, MDR1, ABC transporters, selective sweeps, loss of heterozygosity, karyotype changes, DNA fingerprinting, minimum inhibitory concentration
MeSH terms
Antifungal Agents, Candida albicans, Candidiasis, Oral, Culture Media, Drug Resistance, Microbial, Humans, Karyotyping, Microbial Sensitivity Tests, Colony Count, Microbial, Fluconazole, DNA Fingerprinting, AIDS-Related Opportunistic Infections, Sequence Analysis, DNA, Evolution, Molecular, Loss of Heterozygosity

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