title: Genetic Drivers of Multidrug Resistance inCandida glabrata.
abstract: Both the incidence of invasive fungal infections and rates of multidrug resistance associated with fungal pathogenCandida glabratahave increased in recent years. In this perspective, we will discuss the mechanisms underlying the capacity ofC. glabratato rapidly develop resistance to multiple drug classes, including triazoles and echinocandins. We will focus on the extensive genetic diversity among clinical isolates ofC. glabrata, which likely enables this yeast to survive multiple stressors, such as immune pressure and antifungal exposure. In particular, over half ofC. glabrataclinical strains collected from U.S. and non-U.S. sites have mutations in the DNA mismatch repair geneMSH2, leading to a mutator phenotype and increased frequencies of drug-resistant mutantsin vitro. Furthermore, recent studies and data presented here document extensive chromosomal rearrangements amongC. glabratastrains, 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 inC. glabrata in vivoduring the course of antifungal treatment. Interestingly, we also show that bothMSH2genotypes and chromosomal patterns cluster consistently into specific strain types, indicating thatC. glabratahas a complex population structure where genomic variants arise, perhaps during the process of adaptation to environmental changes, and persist over time.
authors.affiliation: Public Health Research Institute, Rutgers Biomedical and Health Sciences, New Jersey Medical School Newark, NJ, USA.
authors.forename: Kelley R
authors.initials: KR
authors.lastname: Healey
authors.affiliation: Public Health Research Institute, Rutgers Biomedical and Health Sciences, New Jersey Medical School Newark, NJ, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Jimenez Ortigosa
authors.affiliation: Public Health Research Institute, Rutgers Biomedical and Health Sciences, New Jersey Medical School Newark, NJ, USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Shor
authors.affiliation: Public Health Research Institute, Rutgers Biomedical and Health Sciences, New Jersey Medical School Newark, NJ, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Perlin
keywords: Candida glabrata; DNA repair; MLST genotyping; MSH2; antifungal resistance; echinocandins; karyotyping; triazoles