Systematic Screening of a Glycolysis-targeting Small-molecule Library Identifies Novel Inhibitors of Fungal Morphogenesis in Candida albicans

Comparative RNA-Seq analysis revealed significant perturbation of glycolysis following PKM2-IN-6 treatment, while molecular docking analysis predicted that these compounds bind to specific pockets of pyruvate kinase in C. albicans. Interestingly, PKM2-IN-6 treatment resulted in the repression of multiple genes associated with fungal morphogenesis, biofilm formation, and virulence. These transcriptional changes were accompanied by a significant reduction in biofilm formation and increased sensitivity to conventional antifungal drugs, including amphotericin B and fluconazole, in the presence of both the compounds, PKM2-IN-6 and NPD10084.

Furthermore, administration of PKM2-IN-6 significantly improved the survival of mice in a systemic model of murine candidiasis underscoring the in vivo efficacy of this compound. Collectively, our study has identified novel small-molecules that target fungal morphogenesis and virulence in C. albicans, establishing inhibition of glycolysis as a potent antifungal strategy.