thiolactomycin and Klebsiella-Infections

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.

Topics: 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; Animals; Anti-Bacterial Agents; Burkholderia pseudomallei; Cell Line; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Francisella tularensis; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Molecular Conformation; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship; Thiophenes; Yersinia pestis