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Discovery and Optimization of Novel SaFabI Inhibitors as Specific Therapeutic Agents for MRSA Infection.
Zhang, Laiying; Yang, Jiaxing; Xu, Xin; Zhang, Jiangnan; Qiu, Zhiqiang; Ju, Yuan; Luo, Baozhu; Liu, Yan; Gou, Xupeng; Sui, Jing; Chen, Baoyi; Wang, Yanmei; Tao, Tao; He, Lei; Yang, Tao; Luo, Youfu.
Afiliación
  • Zhang L; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • Yang J; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • Xu X; 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.
  • Zhang J; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • Qiu Z; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • Ju Y; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • Luo B; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • Liu Y; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • Gou X; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • Sui J; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • Chen B; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • Wang Y; Institute of traditional Chinese medicine, Sichuan College of Traditional Chinese Medicine, The Second Hospital of Traditional Chinese Medicine in Sichuan Province, Chengdu 610041, China.
  • Tao T; Institute of traditional Chinese medicine, Sichuan College of Traditional Chinese Medicine, The Second Hospital of Traditional Chinese Medicine in Sichuan Province, Chengdu 610041, China.
  • He L; Institute of traditional Chinese medicine, Sichuan College of Traditional Chinese Medicine, The Second Hospital of Traditional Chinese Medicine in Sichuan Province, Chengdu 610041, China.
  • Yang T; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • Luo Y; Laboratory of Human Diseases and Immunotherapies, West China Hospital, Sichuan University, Chengdu 610041, China.
J Med Chem ; 67(12): 10096-10134, 2024 Jun 27.
Article en En | MEDLINE | ID: mdl-38845361
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Infecciones Estafilocócicas / Pruebas de Sensibilidad Microbiana / Staphylococcus aureus Resistente a Meticilina / Descubrimiento de Drogas / Antibacterianos Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Infecciones Estafilocócicas / Pruebas de Sensibilidad Microbiana / Staphylococcus aureus Resistente a Meticilina / Descubrimiento de Drogas / Antibacterianos Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos