Research Projects

Invasive fungal infections, that cause more than 2.5 million deaths annually, pose a major threat to human health. The current antifungal arsenal, that is rather limited, majorly consists of ergosterol biosynthesis-inhibitory azole, ergosterol-binding polyene and cell wall biosynthesis-inhibitory echinocandin drugs. The emerging co-resistance to azole and echinocandin drugs in the high-priority fungal pathogen Candida glabrata (Nakaseomyces glabratus) is of great concern, as the mortality rate associated with antifungal-resistant C. glabrata (Cg) infections can exceed 60%. Our recent findings have revealed a pivotal role for core histone proteins and histone H3-lysine modification enzymes in antifungal resistance in Cg, with core histone gene dosage reduction and histone H3K36 methyltransferase loss, respectively, leading to increased and decreased susceptibility to echinocandin and azole drugs. A full mechanistic understanding of epigenetic regulatory mechanisms in drug resistance in Cg is essential to mitigate the progressively increasing failure of antifungal therapy in hospital settings worldwide. Thus, the current proposal is aimed at a molecular understanding of how the variant and core histone proteins and their posttranslational modifications control expression of the genes that encode the azole resistance transcriptional regulator (CgPdr1), ergosterol biosynthesis gene regulator (CgUpc2a), and echinocandin drug targets (CgFks1 and CgFks2), followed by extending the analysis to Indian Cg clinical isolates. Besides advancing our knowledge of clinical drug resistance mechanisms and unveiling new antifungal targets, the study may potentially identify strategies that can potentially thwart the emergence of azole and echinocandin resistance in Cg under clinical settings.