Deep mutationnal scanning of Candida albicans Erg11

Azole 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 are a common resistance mechanism in most Candida spp. How many and which mutations confer resistance is however largely unknown. Here, we measure the impact of nearly 4,000 amino acid variants of the Candida albicans Erg11 (Cyp51) 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%).