Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance

Abstract

The fungal pathogen Candida glabrata has emerged as a major health threat since it readily acquires resistance to multiple drug classes, including triazoles and/or echinocandins. Thus far, cellular mechanisms promoting the emergence of resistance to multiple drug classes have not been described in this organism. Here we demonstrate that a mutator phenotype caused by a mismatch repair defect is prevalent in C. glabrata clinical isolates. Strains carrying alterations in mismatch repair gene MSH2 exhibit a higher propensity to breakthrough antifungal treatment in vitro and in mouse models of colonization, and are recovered at a high rate (55% of all C. glabrata recovered) from patients. This genetic mechanism promotes the acquisition of resistance to multiple antifungals, at least partially explaining the elevated rates of triazole and multi-drug resistance associated with C. glabrata. We anticipate that identifying MSH2 defects in infecting strains may influence the management of patients on antifungal drug therapy.

Rapid Detection of FKS -Associated Echinocandin Resistance in Candida glabrata

“…FKS1 HS1 and FKS2 HS1 regions were amplified and sequenced in both directions as previously described (17).…”

In Vitro Exposure to Increasing Micafungin Concentrations Easily Promotes Echinocandin Resistance in Candida glabrata Isolates

“…Genotyping showed that isolates were identical before and after micafungin progressive exposure, thus excluding any potential contamination of the isolates during the propagation steps. The emergence of echinocandin resistance could be caused by the predisposition of this pathogen to easily acquire mutations in response to drug pressure due to its haploid nature and to alterations caused by mismatched repair genes (15). The five isolates studied became echinocandin resistant when grown even on plates containing low concentrations of micafungin.…”

For Debate: May the Use of the Polyene Macrolide Natamycin as a Food Additive Foster Emergence of Polyene-Resistance in Candida Species?

“…Alterations in sterol-and phospholipid composition as well as changes in membrane structure account for different polyene-cross-resistance patterns [130,131] and were found in clinical isolates resistant to Azoles as well as polyenes [98,[132][133][134][135][136][137]. The situation is probably aggravated by the finding that a mutator phenotype caused by a mismatch repair defect is prevalent in C. glabrata [138]. This genetic mechanism promotes the acquisition of resistance to multiple antifungals.…”