Discovery and Optimization of Novel Sa FabI Inhibitors as Specific Therapeutic Agents for MRSA Infection.

As the rate-limiting enzyme in fatty acid biosynthesis, Staphylococcus aureus enoyl-acyl carrier protein reductase ( Sa FabI) emerges as a compelling target for combating methicillin-resistant S. aureus (MRSA) infections. Herein, compound 1 , featuring a 4-(1 H -benzo[ d ]imidazol-2-yl)pyrrolidin-2-one scaffold, was identified as a potent Sa FabI inhibitor (IC 50 = 976.8 nM) from an in-house library. Subsequent optimization yielded compound n31 , with improved inhibitory efficacy on enzymatic activity (IC 50 = 174.2 nM) and selective potency against S. aureus (MIC = 1-2 μg/mL). Mechanistically, n31 directly inhibited Sa FabI in cellular contexts. Moreover, n31 exhibited favorable safety and pharmacokinetic profiles, and dose-dependently treated MRSA-induced skin infections, outperforming the approved drug, linezolid. The chiral separation of n31 resulted in ( S )-n31 , with superior activities (IC 50 = 94.0 nM, MIC = 0.25-1 μg/mL) and in vivo therapeutic efficacy. In brief, our research proposes ( S )-n31 as a promising candidate for Sa FabI-targeted therapy, offering specific anti- S. aureus efficacy and potential for further development.