September 28, 2022

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Nature Reviews Microbiology (2022)
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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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Després, P. C. et al. Asymmetrical dose responses shape the evolutionary trade-off between antifungal resistance and nutrient use. Nat. Ecol. Evol. (2022)
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Nature Reviews Microbiology
Grant Otto
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Correspondence to Grant Otto.
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Otto, G. Fitness cost of antifungal resistance. Nat Rev Microbiol (2022).
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Nature Reviews Microbiology (Nat Rev Microbiol) ISSN 1740-1534 (online) ISSN 1740-1526 (print)
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