Genetic Drivers of Multidrug Resistance in .

Both the incidence of invasive fungal infections and rates of multidrug resistance associated with fungal pathogen have increased in recent years. In this perspective, we will discuss the mechanisms underlying the capacity of to rapidly develop resistance to multiple drug classes, including triazoles and echinocandins. We will focus on the extensive genetic diversity among clinical isolates of , which likely enables this yeast to survive multiple stressors, such as immune pressure and antifungal exposure. In particular, over half of clinical strains collected from U.S. and non-U.S. sites have mutations in the DNA mismatch repair gene , leading to a mutator phenotype and increased frequencies of drug-resistant mutants . Furthermore, recent studies and data presented here document extensive chromosomal rearrangements among strains, resulting in a large number of distinct karyotypes within a single species. By analyzing clonal, serial isolates derived from individual patients treated with antifungal drugs, we were able to document chromosomal changes occurring in during the course of antifungal treatment. Interestingly, we also show that both genotypes and chromosomal patterns cluster consistently into specific strain types, indicating that has a complex population structure where genomic variants arise, perhaps during the process of adaptation to environmental changes, and persist over time.