Abstract
AbstractAzole antifungals are among the most frequently used drugs to treat fungal infections. Amino acid substitutions in and around the binding site of the azole target Erg11 (Cyp51) are a common resistance mechanism in pathogenic yeasts such asCandida albicans. How many and which mutations confer resistance, and at what cost, is however largely unknown. Here, we measure the impact of nearly 4,000 amino acid variants of the Erg11 ligand binding pocket on the susceptibility to six medical azoles. We find that a large fraction of amino acid substitutions lead to resistance (33%), most resistance mutations confer cross-resistance to two or more azoles (88%) and most importantly, only a handful of resistance mutations show a significant fitness cost in the absence of drug (9%). Our results reveal that selection for azole resistance can arise through a large set of mutations and this will likely lead to azole pan-resistance, with very little evolutionary compromise. Such a resource will help inform treatment choices in clinical settings and guide the development of new drugs.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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