P154: New Type of Enoyl-ACP Reductase Inhibitor with Anti-MRSA Activity isolated from Penicillium sp

Bacterial enoyl-ACP reductase that catalyzes the final and rate-limiting step in the type II fatty acid synthesis has been validated as a novel target for antibacterial drug development. There are three isoforms, FabI, FabK and FabL, of enoyl-ACP reductase. FabI is highly conserved among most bacteria. Our screening program for new FabI inhibitors led to the selection of Penicillium sp. producing a strong inhibitory metabolite. The active compound was purified as a single compound through bioassay-guided fractionation. Its chemical structure was elucidated to be vinaxanthone. It selectively inhibited Staphylococcus aureus FabI with an IC₅₀ of 0.9 uM, while didn’t effect FabK. Consistent with its inhibition of FabI, the inhibitor prevented intracellular fatty acid synthesis as well as the growth of S. aureus, MRSA, and QRSA with MIC of 32µg/mL. Importantly, FabI-overexpressing S. aureus showed reduced susceptibility to the inhibitor compared to wild strain, confirming that its antibacterial action is mediated by the inhibition of FabI. In conclusion, vinaxanthone is a new type of FabI-directed antibacterial of microbial origin. This work was supported by the 21C Frontier Microbial Genomics and Application Center Program.