Azole antifungals are the main drugs used to treat fungal infections. Amino acid substitutions in the drug target Erg11 (Cyp51) are a common resistance mechanism in pathogenic yeasts. How many and which mutations confer resistance is, however, largely unknown. Here we measure the impact of nearly 4,000 amino acid variants of Candida albicans Erg11 on the susceptibility to six clinical azoles. This was achieved by deep mutational scanning of CaErg11 expressed in Saccharomyces cerevisiae. We find that a large fraction of mutations lead to resistance (33%), most resistance mutations confer cross-resistance (88%) and only a handful of resistance mutations show a significant fitness cost (9%). Our results reveal that resistance to azoles can arise through a large set of mutations and this will probably lead to azole pan-resistance, with little evolutionary compromise. This resource will help inform treatment choices in clinical settings and guide the development of new drugs.

唑类抗真菌药是用于治疗真菌感染的主要药物。药物靶标 Erg11 （Cyp51） 中的氨基酸取代是病原酵母菌中的常见耐药机制。然而，有多少突变以及哪些突变会产生耐药性在很大程度上是未知的。在这里，我们测量了白色念珠菌 Erg11 的近 4,000 个氨基酸变体对六种临床唑类药物易感性的影响。这是通过对酿酒酵母中表达的 CaErg11 进行深度突变扫描来实现的。我们发现，很大一部分突变导致耐药 （33%），大多数耐药突变赋予交叉耐药 （88%），只有少数耐药突变显示出显着的适应成本 （9%）。我们的结果表明，对唑类药物的耐药性可以通过大量突变产生，这可能会导致唑类泛耐药性，而进化上几乎没有妥协。该资源将有助于为临床环境中的治疗选择提供信息并指导新药的开发。