Molecular investigations on Candida glabrata clinical isolates for pharmacological targeting

Abstract

Prevalence of drug resistant C. glabrata strains in hospitalized immune-compromised patients with invasive fungal infections has increased at an unexpected pace. This has greatly pushed researchers in identification of mutations/variations in clinical isolates for better assessment of the prevailing drug resistance trends and also for updating of antifungal therapy regime. In the present investigation, the clinical isolates of C. glabrata were comprehensively characterized at a molecular level using metabolic profiling and transcriptional expression analysis approaches in combination with biochemical, morphological and chemical profiling methods. Biochemically, significant variations in azole susceptibility, surface hydrophobicity, and oxidative stress generation were observed among the isolates as compared to wild-type. The ¹H NMR profiling identified 18 differential metabolites in clinical strains compared to wild-type and were classified into five categories, that include: sugars (7), amino acids and their derivatives (7), nitrogen bases (3) and coenzymes (1). Transcriptional analysis of selective metabolic and regulatory enzymes established that the major differences were found in cell membrane stress, carbohydrate metabolism, amino acid biosynthesis, ergosterol pathway and turnover of nitrogen bases. This detailed molecular level/metabolic fingerprint study is a useful approach for differentiating pathogenic/clinical isolates to that of wild-type. This study comprehensively delineated the differential cellular pathways at a molecular level that have been re-wired by the pathogenic clinical isolates for enhanced pathogenicity and virulence traits.