Late-Stage Functionalization of Platensimycin Leading to Multiple Analogues with Improved Antibacterial Activity in Vitro and in Vivo

Abstract

Bacterial fatty acid synthases are promising antibacterial targets against multidrug-resistant pathogens. Platensimycin (PTM) is a potent FabB/FabF inhibitor, while its poor pharmacokinetics hampers the clinical development. In this study, a focused library of PTM derivatives was prepared through thiolysis of PTM oxirane (<b>1</b>), followed by various C-C cross-coupling reactions in high yields. Antibacterial screening of these compounds in vitro yielded multiple hits with improved anti-<i>Staphylococcus</i> activities over PTM. Among them, compounds <b>A1</b>, <b>A3</b>, <b>A17</b>, and <b>A28</b> exhibited improved antibacterial activities over PTM against methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) in a mouse peritonitis model. Compound <b>A28</b> was further shown to be effective against MRSA infection in a mouse wound model, in comparison to mupirocin. Therefore, the facile preparation and screening of these PTM derivatives, together with their potent antibacterial activities in vivo, suggest a promising strategy to improve the antibacterial activity and pharmacokinetic properties of PTM.