Characterization of an allosteric inhibitor of fungal-specific C-24 sterol methyltransferase to treat Candida albicans infections.

Filamentation is an important virulence factor of the pathogenic fungus Candida albicans. The abolition of Candida albicans hyphal formation by disrupting sterol synthesis is an important concept for the development of antifungal drugs with high safety. Here, we conduct a high-throughput screen using a C. albicans strain expressing green fluorescent protein-labeled Dpp3 to identify anti-hypha agents by interfering with ergosterol synthesis. The antipyrine derivative H55 is characterized to have minimal cytotoxicity and potent inhibition of C. albicans hyphal formation in multiple cultural conditions. H55 monotherapy exhibits therapeutic efficacy in mouse models of azole-resistant candidiasis. H55 treatment increases the accumulation of zymosterol, the substrate of C-24 sterol methyltransferase (Erg6). The results of enzyme assays, photoaffinity labeling, molecular simulation, mutagenesis, and cellular thermal shift assays support H55 as an allosteric inhibitor of Erg6. Collectively, H55, an inhibitor of the fungal-specific enzyme Erg6, holds potential to treat C. albicans infections. [Display omitted] • High-throughput screening for Dpp3 inducers identifies H55, an inhibitor of Erg6 • H55 inhibits adhesion, hyphal growth, and biofilm formation of Candida albicans • H55 exhibits therapeutic efficacy validating Erg6 as a therapeutic target Jin et al. report that the antipyrine derivative H55 is an inhibitor of Erg6 to neutralize the virulence of C. albicans. H55 exhibits therapeutic efficacy in murine candidiasis models and has high biological safety because Erg6 is absent from human cells. [ABSTRACT FROM AUTHOR]