Asymmetrical dose responses shape the evolutionary trade-off between antifungal resistance and nutrient use
Open accessPublished version of a preprint
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-fluorocytosine (5-FC, flucytosine). We identify over 900 missense mutations granting resistance to 5-FC, a large fraction of which appear to act through destabilization 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 orthologue 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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Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
ColabFold - Making protein folding accessible to all
Mirdita, M., Schütze, K., Moriwaki, Y., Heo, L., Ovchinnikov, S., & Steinegger, M. (2021) · doi:10.1101/2021.08.15.456425 · Cited by 9,391 · see citing works
seaborn: statistical data visualization
Waskom, M. (2021) · Journal of Open Source Software · doi:10.21105/joss.03021 · Cited by 7,310 · see citing works
The FoldX web server: an online force field
Schymkowitz, J., Borg, J., Stricher, F., Nys, R., Rousseau, F., & Serrano, L. (2005) · Nucleic Acids Research · doi:10.1093/nar/gki387 · Cited by 2,759 · see citing works
PANDAseq: paired-end assembler for Illumina sequences
Masella, A. P., Bartram, A. K., Truszkowski, J. M., Brown, D. G., & Neufeld, J. D. (2012) · BMC Bioinformatics · doi:10.1186/1471-2105-13-31 · Cited by 2,132 · see citing works
BRENDA, the ELIXIR core data resource in 2021: new developments and updates
Chang, A., Jeske, L., Ulbrich, S., Hofmann, J., Koblitz, J., Schomburg, I., Neumann-Schaal, M., Jahn, D., & Schomburg, D. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkaa1025 · Cited by 789 · see citing works
Treatment strategies for cryptococcal infection: challenges, advances and future outlook
Iyer, K. R., Revie, N. M., Fu, C., Robbins, N., & Cowen, L. E. (2021) · Nature Reviews Microbiology · doi:10.1038/s41579-021-00511-0 · Cited by 363 · see citing works
World Health Organization model list of essential medicines for children 8th list, 2021
Organization, W.-H. (2022) · Yearbook of Paediatric Endocrinology · doi:10.1530/ey.19.13.1 · Cited by 351 · see citing works
Ksiezopolska, E., Schikora-Tamarit, M. À., Beyer, R., Nunez-Rodriguez, J. C., Schüller, C., & Gabaldón, T. (2021) · Current Biology · doi:10.1016/j.cub.2021.09.084 · Cited by 107 · see citing works
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- Authors
- Després, P. C., Cisneros, A. F., Alexander, E. M. 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
- Published
- 2022-09-01
- Volume
- 6
- Issue
- 10
- Pages
- 1501-1515
- ISSN
- 2397-334X (ISSN-L)
- OpenAlex
- W4294053447
- Cited by
- 32
- References
- 9
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 13 · 2023: 5 · 2022: 1
- FWCI
- 3.06
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- 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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