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ANTIMICROBIAL RESISTANCE

Fitness cost of antifungal resistance

Nature Reviews Microbiology volume 20, page 637 (2022)Cite this article

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Antifungal resistance is an increasing concern for human health and agriculture, but the resistance–fitness trade-offs of mutations conferring resistance and the molecular mechanisms of their effects are unclear. Després et al. use deep mutational scanning to perform a comprehensive cost:benefit analysis of all single-codon mutations of the yeast cytosine deaminase Fcy1, an enzyme that converts the antifungal prodrug 5-fluorocytosine (5-FC) to the active drug 5-fluorouracil, but is also important for cytosine and cytidine metabolism. 5-FC-resistance-conferring mutations occurred throughout the protein, many of which affected protein stability (resulting in loss-of-function phenotypes) and, importantly, substantially reduced fitness in conditions where Fcy1 is essential, even when resistance gains were small. This strong resistance–function trade-off was conserved for the Cryptococcus neoformans Fcy1 orthologue. This approach could facilitate prediction of the fitness effects of drug target variants in fungal pathogens.

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  1. Nature Reviews Microbiology http://www.nature.com/nrmicro/

    Grant Otto

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  1. Grant Otto
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Correspondence to Grant Otto.

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Otto, G. Fitness cost of antifungal resistance. Nat Rev Microbiol 20, 637 (2022). https://doi.org/10.1038/s41579-022-00800-2

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  • DOI: https://doi.org/10.1038/s41579-022-00800-2

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