Pantothenate kinase is an effective target for antifungal therapy

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.