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

• Published in: Antimicrobial agents and chemotherapy 2018-06, Vol.62 (6)
• Main Authors: Singh, Ashutosh, Healey, Kelley R, Yadav, Priyanka, Upadhyaya, Gargi, Sachdeva, Neelam, Sarma, Smita, Kumar, Anil, Tarai, Bansidhar, Perlin, David S, Chowdhary, Anuradha
• Format: Article
• Language: English
• Subjects: Anidulafungin - pharmacology; Antifungal Agents; Antifungal Agents - pharmacology; Azoles; Azoles - pharmacology; Candida glabrata; Candida glabrata - drug effects; Candida glabrata - genetics; Candida glabrata - isolation & purification; Candidiasis - drug therapy; Candidiasis - microbiology; Caspofungin - pharmacology; DNA Mismatch Repair - genetics; Drug Resistance, Fungal; Drug Resistance, Fungal - genetics; Echinocandins; Echinocandins - pharmacology; Humans; India; Mechanisms of Resistance; Micafungin - pharmacology; Microbial Sensitivity Tests; Mutation - genetics
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.00195-18

infections are increasing worldwide and exhibit greater rates of antifungal resistance than those with other species. DNA mismatch repair (MMR) gene deletions, such as , in 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 isolates in 10 hospitals in India and investigated the impact of novel polymorphisms on mutation potential. No echinocandin- or azole-resistant strains and no mutations in hot spot regions were detected among the isolates, supporting our susceptibility testing results. CLSI antifungal susceptibility data showed that the MICs of anidulafungin (geometric mean [GM], 0.12 μg/ml) and micafungin (GM, 0.01 μg/ml) were lower and below the susceptibility breakpoint compared to that of caspofungin (CAS) (GM, 1.31 μg/ml). Interestingly, 69% of the strains sequenced contained six nonsynonymous mutations in , i.e., V239L and the novel mutations E459K, R847C, Q386K, T772S, and V239/D946E. Functional analysis of mutations revealed that 49% of the tested strains (40/81) contained a partial loss-of-function mutation. The novel substitution Q386K produced higher frequencies of CAS-resistant colonies upon expression in the mutant. However, expression of two other novel alleles, i.e., E459K or R847C, did not confer selection of resistant colonies, confirming that not all mutations in the 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 genotype.