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- W3215156790 abstract "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." @default.
- W3215156790 created "2021-12-06" @default.
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- W3215156790 date "2021-11-29" @default.
- W3215156790 modified "2023-10-14" @default.
- W3215156790 title "Asymmetrical dose-responses shape the evolutionary trade-off between antifungal resistance and nutrient use" @default.
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- W3215156790 doi "https://doi.org/10.1101/2021.11.29.469899" @default.
- W3215156790 hasPublicationYear "2021" @default.
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