Antibacterial tricyclic peptides inhibiting fatty acid synthesis from Streptomyces sp.

Bacterial fatty acid synthesis (FAS II) has been as an attractive antibacterial target since FAS is organized differently in bacteria and mammals. Bacterial enoyl-ACP reductase (FabI) 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. Our screening program led to the selection of Streptomyces sp. producing FabI-inhibitory metabolites. The chemical structures of the isolated FabI inhibitors were elucidated by mass (MS) and nuclear magnetic resonance (NMR) spectral data. Antibacterial target of the inhibitors was examined using FabI inhibition, macromolecular biosynthesis, and supplementation assay. The isolated FabI inhibitors were elucidated to be tricyclic peptides. They strongly inhibited Staphylococcus aureus FabI with IC_50s (uM) of 0.1 - 0.2. The compounds also potently prevented the growth of S. aureus as well as methicillin-resistant S. aureus (MRSA) and quinolone-resistant S. aureus (QRSA) with MICs (mg/L) of 1 - 4. Time-kill study showed its bacteriostatic activity. Consistent with its FabI inhibition, the inhibitor selectively prevented intracellular fatty acid synthesis, whereas did not affect the biosynthesis of DNA, RNA, protein, and cell wall. Furthermore, the supplementation with exogenous fatty acids reversed the antibacterial effect of the compound, which showing that they target fatty acid synthesis. Our data demonstrate that the antibacterial action of the compounds is mediated by the inhibition of fatty acid synthesis. The compounds are a new type of fatty acid synthesis inhibitors that could have potential for further development of a new anti-MRSA agent.