Absence of azole or echinocandin resistance in candida glabrata isolates in India despite background prevalence of strains with defects in the dna mismatch repair pathway

Ashutosh Singh, Kelley R. Healey, Priyanka Yadav, Gargi Upadhyaya, Neelam Sachdeva, Smita Sarma, Anil Kumar, Bansidhar Tarai, David S. Perlin, Anuradha Chowdhary

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28 Scopus citations

Abstract

Candida glabrata infections are increasing worldwide and exhibit greater rates of antifungal resistance than those with other species. DNA mismatch repair (MMR) gene deletions, such as msh2, in C. glabrata resulting in a mutator phenotype have recently been reported to facilitate rapid acquisition of antifungal resistance. This study determined the antifungal susceptibility profiles 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 and no mutations in FKS hot spot regions were detected among the C. glabrata isolates, supporting our in vitro susceptibility testing results. CLSI antifungal susceptibility data showed that the MICs of anidulafungin (geometric mean [GM], 0.12 g/ml) and micafungin (GM, 0.01 g/ml) were lower and below the susceptibility breakpoint compared to that of caspofungin (CAS) (GM, 1.31 g/ml). Interestingly, 69% of the C. glabrata strains sequenced contained six nonsynonymous mutations in MSH2, i.e., V239L and the novel mutations E459K, R847C, Q386K, T772S, and V239/D946E. Functional analysis of MSH2 mutations revealed that 49% of the tested strains (40/81) contained a partial loss-of-function MSH2 mutation. The novel MSH2 substitution Q386K produced higher frequencies of CAS-resistant colonies upon expression in the msh2 mutant. 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 the MSH2 MMR pathway affect its function or generate a phenotype of resistance to antifungal drugs. The lack of drug resistance prevented any correlations from being drawn with respect to MSH2 genotype.

Original languageEnglish (US)
Article numbere00195-18
JournalAntimicrobial agents and chemotherapy
Volume62
Issue number6
DOIs
StatePublished - Jun 2018

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Keywords

  • Candida glabrata
  • Echinocandins
  • FKS
  • India
  • MSH2
  • Mismatch repair
  • Mutator genotype

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