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

Nat Ecol Evol. 2022 Oct;6(10):1501-1515. doi: 10.1038/s41559-022-01846-4. Epub 2022 Sep 1.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Antifungal Agents* / pharmacology
  • Cytosine
  • Cytosine Deaminase / genetics
  • Cytosine Deaminase / metabolism
  • Cytosine Deaminase / pharmacology
  • Flucytosine* / pharmacology
  • Nutrients
  • Saccharomyces cerevisiae / genetics

Substances

  • Antifungal Agents
  • Cytosine
  • Flucytosine
  • Cytosine Deaminase