Cell chemical biology · 2025
Pantothenate kinase is an effective target for antifungal therapy.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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Regan Jessica, DeJarnette Christian, Reitler Parker, Gihaz Shalev, Srivastava Ashish, Ge Wenbo, Tucker Katie M, Peters Tracy L, Meibohm Bernd, Ben Mamoun Choukri, Fortwendel Jarrod R, Hevener Kirk E, Palmer Glen E
Аннотация
Pantothenate kinase (PanK) catalyzes the first step in the conversion of pantothenate to coenzyme A (CoA), an essential cofactor in all living organisms. The findings of this study demonstrate that PanK is essential for the viability and virulence of two of the most medically significant fungi-the pathogenic yeast Candida albicans, and the infectious mold Aspergillus fumigatus-within the mammalian host. Biochemical, biophysical as well as chemical-genetic approaches were applied to identify 3,4-methylenedioxy-β-nitrostyrene (MNS) as a broad-spectrum antifungal that directly engages and inhibits PanK to block CoA production. Importantly, MNS is inactive against a mammalian PanK and demonstrates in vivo antifungal efficacy a mouse model of disseminated C. albicans infection. Thus, MNS has provided a valuable chemical probe to establish the validity of targeting PanK with small molecule inhibitors as a strategy to develop efficacious antifungal therapeutics.