Thiolactomycin-Based Inhibitors of Bacterial β-Ketoacyl-ACP Synthases with in Vivo Activity
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- 作者：Gopal R. Bommineni ; Kanishk Kapilashrami ; Jason E. Cummings ; Yang Lu ; Susan E. Knudson ; Chendi Gu ; Stephen G. Walker ; Richard A. Slayden ; Peter J. Tonge
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：June 9, 2016
- 年：2016
- 卷：59
- 期：11
- 页码：5377-5390
- 全文大小：647K
- 年卷期：0
- ISSN：1520-4804
文摘
β-Ketoacyl-ACP synthases (KAS) are key enzymes involved in the type II bacterial fatty acid biosynthesis (FASII) pathway and are putative targets for antibacterial discovery. Several natural product KAS inhibitors have previously been reported, including thiolactomycin (TLM), which is produced by Nocardia spp. Here we describe the synthesis and characterization of optically pure 5R-thiolactomycin (TLM) analogues that show improved whole cell activity against bacterial strains including methicillin-resistant Staphylococcus aureus (MRSA) and priority pathogens such as Francisella tularensis and Burkholderia pseudomallei. In addition, we identify TLM analogues with in vivo efficacy against MRSA and Klebsiella pneumoniae in animal models of infection.