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

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

  • J Med Chem. 2024 Jun 27;67(12):10096-10134. doi: 10.1021/acs.jmedchem.4c00320.
Laiying Zhang 1,  Jiaxing Yang 1,  Xin Xu 2,  Jiangnan Zhang 1,  Zhiqiang Qiu 1,  Yuan Ju 1,  Baozhu Luo 1,  Yan Liu 1,  Xupeng Gou 1,  Jing Sui 1,  Baoyi Chen 1,  Yanmei Wang 3,  Tao Tao 3,  Lei He 3,  Tao Yang 1 4 5,  Youfu Luo 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2 Editorial Office of Chinese Journal of Medical Genetics, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, China.
  • 3 Institute of traditional Chinese medicine, Sichuan College of Traditional Chinese Medicine, The Second Hospital of Traditional Chinese Medicine in Sichuan Province, Chengdu 610041, China.
  • 4 Laboratory of Human Diseases and Immunotherapies, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 5 Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
PMID: 38845361 DOI: 10.1021/acs.jmedchem.4c00320
Abstract

As the rate-limiting Enzyme in fatty acid biosynthesis, Staphylococcus aureus enoyl-acyl carrier protein reductase (SaFabI) emerges as a compelling target for combating methicillin-resistant S. aureus (MRSA) infections. Herein, compound 1, featuring a 4-(1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one scaffold, was identified as a potent SaFabI inhibitor (IC50 = 976.8 nM) from an in-house library. Subsequent optimization yielded compound n31, with improved inhibitory efficacy on enzymatic activity (IC50 = 174.2 nM) and selective potency against S. aureus (MIC = 1-2 μg/mL). Mechanistically, n31 directly inhibited SaFabI 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 (IC50 = 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 SaFabI-targeted therapy, offering specific anti-S. aureus efficacy and potential for further development.

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