Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance.
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.
Healey, KR; Zhao, Y; Perez, WB; Lockhart, SR; Sobel, JD; Farmakiotis, D; Kontoyiannis, DP; Sanglard, D; Taj-Aldeen, SJ; Alexander, BD; Jimenez-Ortigosa, C; Shor, E; Perlin, DS
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