Genetic Drivers of Multidrug Resistance in Candida glabrata.

Kelley R Healey,David S Perlin,Cristina Jimenez Ortigosa,Erika Shor

doi:10.3389/fmicb.2016.01995

Abstract

Both the incidence of invasive fungal infections and rates of multidrug resistance associated with fungal pathogen Candida glabrata have increased in recent years. In this perspective, we will discuss the mechanisms underlying the capacity of C. glabrata to rapidly develop resistance to multiple drug classes, including triazoles and echinocandins. We will focus on the extensive genetic diversity among clinical isolates of C. glabrata, which likely enables this yeast to survive multiple stressors, such as immune pressure and antifungal exposure. In particular, over half of C. glabrata clinical strains collected from U.S. and non-U.S. sites have mutations in the DNA mismatch repair gene MSH2, leading to a mutator phenotype and increased frequencies of drug-resistant mutants in vitro. Furthermore, recent studies and data presented here document extensive chromosomal rearrangements among C. glabrata 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 C. glabrata in vivo during the course of antifungal treatment. Interestingly, we also show that both MSH2 genotypes and chromosomal patterns cluster consistently into specific strain types, indicating that C. glabrata has a complex population structure where genomic variants arise, perhaps during the process of adaptation to environmental changes, and persist over time.

Highlights

Public Health Research Institute, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Newark, NJ, USA
A multi-locus sequence typing (MLST) scheme based on six different loci has far identified over 80 different C. glabrata sequence types (STs, or clades) (Dodgson et al, 2003) and our preliminary analysis indicates that this number is likely much higher
Accumulating evidence suggests that both increasing numbers of immunocompromised patients and the widespread use of triazoles, fluconazole, have facilitated an increased prevalence of C. glabrata infections and more alarmingly, the emergence of multidrug resistant strains

Summary

GLABRATA POPULATION STRUCTURE

STRAIN TYPES ARE CHARACTERIZED BY SPECIFIC NUCLEOTIDE POLYMORPHISMS AND GENOME REARRANGEMENTS. We found that different msh alleles (see above and Figure 1A) are characteristic of distinct STs/clades, indicating that different STs may have different propensity toward mutability and acquiring drug resistant gene variants. This conclusion is significant because the distribution of C. glabrata STs varies both by geography and over time (Dodgson et al, 2003; Lott et al, 2010). The observation that different C. glabrata STs carry different msh alleles makes it highly likely that other important determinants of drug resistance or virulence vary among STs. A straightforward way to identify such determinants is by genome sequencing. Together with data presented above (Figure 1B), this observation suggests that chromosomal variants of C. glabrata both exist as commensal populations, where different STs are characterized by specific chromosomal configurations, and arise de novo, perhaps in response to pressure from the host and antifungal drug treatment

CONCLUSION

Findings

ETHICS STATEMENT