New antibacterial compounds inhibiting Staphylococcus aureus enoyl-ACP reductase from Penicillium sp.

Bacterial enoyl-ACP reductase (FabI) is an attractive antibacterial target which catalyzes the final and rate-limiting step in bacterial fatty acid synthesis. Therefore, FabI inhibitors could be interesting lead compounds for treatment of multidrug-resistant bacteria. In the course of our screening for FabI inhibitors from microbial resources, a fungal strain Penicillium verruculosum producing FabI-inhibitory and antibacterial metabolites was selected. Five novel metabolites named verrulactones A-E with the known compound, altenuisol, were isolated from the fermentation broth of the fungal strain. Their chemical structures were elucidated by 2D NMR and MS analysis. Verrulactones A and B were dimeric compounds of alternariol. Verrulactones C was a dispiro compound. Verrulactones D and E were highly quaternary and unique compounds. Verrulactones A and B strongly inhibited Staphylococcus aureus enoyl-ACP reductase with an IC₅₀ of 1µM. Verrulactones C-E also showed FabI-inhibition even though weaker than Verrulactones A and B. They, however, didn't inhibit S. aureus FabG, another reductase of bacterial FAS, even at 300µM. It indicated selective inhibition for FabI. Consistent with their FabI inhibitory activity, they also showed inhibition on intracellular fatty acid biosynthesis in S. aureus as well as antibacterial activity against S. aureus and MRSA.