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Δευτέρα 2 Απριλίου 2018

Absence of azole or echinocandin resistance in Candida glabrata isolates in India despite background prevalence of strains with defects in DNA mismatch repair pathway [PublishAheadOfPrint]

Candida glabrata infections are increasing world-wide and exhibit greater rates of antifungal resistance than other species. DNA mismatch repair (MMR) gene deletions, such as msh2, in C. glabrata resulting in a mutator phenotype has recently been reported to facilitate rapid acquisition of antifungal resistance. This study determined the antifungal susceptibility profile of 210 C. glabrata isolates, in 10 hospitals in India and investigated the impact of novel MSH2 polymorphisms on mutation potential. No echinocandin or azole resistant strains were detected among C. glabrata isolates and no mutations in FKS hotspot regions supporting our in vitro susceptibility testing results. CLSI antifungal susceptibility data showed MICs of anidulafungin (GM, 0.12μg/ml) and micafungin (GM, 0.01μg/ml) were lower and below the susceptibility breakpoint as compared to that for caspofungin (CAS GM, 1.31μg/ml). Interestingly, 69% of C. glabrata strains sequenced contained six nonsynonymous mutations in MSH2 i.e., V239L, and novel mutations E459K, R847C, Q386K, and T772S. Functional analysis of MSH2 mutations revealed that 49% of tested strains (40/81) contained a partial loss-of-function MSH2 mutation. The novel MSH2 substitution Q386K produced greater frequencies of CAS- resistant colonies upon expression in msh2. However, expression of two other novel MSH2 alleles i.e., E459K or R847C did not confer selection of resistant colonies confirming that not all mutations in MSH2 MMR pathway affects its function or generate a phenotype that is resistant to antifungal drugs. The lack of drug resistance prevented any correlations to be drawn with respect to MSH2 genotype



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