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

作者：Laiying Zhang, Jiaxing Yang, Xin Xu, Jiangnan Zhang, Zhiqiang Qiu, Yuan Ju, Baozhu Luo, Yan Liu, Xupeng Gou, Jing Sui, Baoyi Chen, Yanmei Wang, Tao Tao, Lei He, Tao Yang, Youfu Luo · 发表于：Journal of Medicinal Chemistry · 年份：2024 · DOI：10.1021/acs.jmedchem.4c00320 · 被引用次数：14 · 研究领域：Antimicrobial Resistance in Staphylococcus、Antibiotic Resistance in Bacteria、Antimicrobial Peptides and Activities

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.