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PreprintCited by 32Antifungal resistance and susceptibilityFungal and yeast genetics researchEvolution and Genetic Dynamics

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Asymmetrical dose-responses shape the evolutionary trade-off between antifungal resistance and nutrient use

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Després, Philippe C, Cisneros, Angel F, Alexander, Emilie MM, Sonigara, Ria, Gagné-Thivierge, Cynthia, Dubé, Alexandre K, Landry, Christian R·2021·Nature Ecology & Evolution
DOI 10.1101/2021.11.29.469899

Preprint — published as 10.1038/s41559-022-01846-4 · Paper page

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Abstract

Antimicrobial resistance is an emerging threat for public health. The success of resistance mutations depends on the trade-off between the benefits and costs they incur. This trade-off is largely unknown and uncharacterized for antifungals. Here, we systematically measure the effect of all amino acid substitutions in the yeast cytosine deaminase Fcy1, the target of the antifungal 5-FC (flucytosine). We identify over 900 missense mutations granting resistance to 5-FC, a large fraction of which appear to act through destabilisation of the protein. The relationship between 5-FC resistance and growth sustained by cytosine deamination is characterized by a sharp trade-off, such that small gains in resistance universally lead to large losses in canonical enzyme function. We show that this steep relationship can be explained by differences in the dose-response functions of 5-FC and cytosine. Finally, we observe the same trade-off shape for the ortholog of FCY1 in Cryptoccocus neoformans , a human pathogen. Our results provide a powerful resource and platform for interpreting drug target variants in fungal pathogens as well as unprecedented insights into resistance-function trade-offs.

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Metadata

Authors
Després, P. C., Cisneros, A. F., Alexander, E. M., Sonigara, R., Gagné-Thivierge, C., Dubé, A. K., & Landry, C. R.
Affiliations
  • PROTEO (CA)
  • Université Laval (CA)
Corresponding author
  • Després, Philippe C
  • Landry, Christian R
ORCID
Venue
Nature Ecology & Evolution
Publisher
openRxiv
Published
2021-11-29
Volume
6
Issue
10
Pages
1501-1515
ISSN
2397-334X (ISSN-L)
DOI
10.1101/2021.11.29.469899
OpenAlex
W4294053447
Cited by
32
References
1
Citations by year
2026: 7 · 2025: 6 · 2024: 13 · 2023: 5 · 2022: 1
FWCI
3.05
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Nature Ecology & Evolution (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • University of California, San Francisco
  • Canadian Institutes of Health Research (387697)
  • Fonds de recherche du Québec – Nature et technologies (2022-PR-298169)
  • National Institute of General Medical Sciences (R01GM129325)
  • National Institute of Allergy and Infectious Diseases
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
antifungal resistance, 5-fluorocytosine, cytosine deaminase, missense mutations, protein destabilization, dose-response relationship, Saccharomyces cerevisiae, Cryptococcus neoformans, fungal pathogens
MeSH terms
Nutrients, Antifungal Agents, Cytosine, Flucytosine, Saccharomyces cerevisiae, Cytosine Deaminase

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