Hotspot gene conversion between FKS1 and FKS2 in echinocandin resistant Candida glabrata serial isolates

Candida glabrata (Nakaseomyces glabratus) is the most common cause of drug-resistant candidemia and is associated with a high mortality rate. Only a few mechanisms of drug resistance are known in C. glabrata, predominantly involving recurrent single nucleotide polymorphisms. The importance of structural variation in acquired drug resistance is not understood. We performed comparative phenotypic and genomic analyses of six serial bloodstream isolates of C. glabrata and identified novel mutations associated with resistance to echinocandins. Critically, we identified a novel gene conversion event between the hotspot 2 regions of FKS1 and FKS2 that was associated with increased resistance to micafungin. We further analyzed 621 publicly available C. glabrata genomes and found three additional examples of structural variation involving FKS1 and FKS2. Ultimately, drug resistance in C. glabrata involves structural variants that are missed with current diagnostic methods and need to be considered when designing and implementing more effective antifungal management strategies.