Thiolactomycin-Based Inhibitors of Bacterial β-Ketoacyl-ACP Synthases with in Vivo Activity

J Med Chem. 2016 Jun 9;59(11):5377-90. doi: 10.1021/acs.jmedchem.6b00236. Epub 2016 May 24.

Abstract

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.

MeSH terms

  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / antagonists & inhibitors*
  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / metabolism
  • Animals
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Burkholderia pseudomallei / drug effects
  • Burkholderia pseudomallei / enzymology
  • Cell Line
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Francisella tularensis / drug effects
  • Francisella tularensis / enzymology
  • Humans
  • Klebsiella Infections / drug therapy
  • Klebsiella pneumoniae / drug effects
  • Klebsiella pneumoniae / enzymology
  • Male
  • Methicillin-Resistant Staphylococcus aureus / drug effects
  • Methicillin-Resistant Staphylococcus aureus / enzymology
  • Mice
  • Microbial Sensitivity Tests
  • Molecular Conformation
  • Staphylococcal Infections / drug therapy
  • Staphylococcus aureus / drug effects
  • Staphylococcus aureus / enzymology
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis
  • Thiophenes / chemistry
  • Thiophenes / pharmacology
  • Yersinia pestis / drug effects
  • Yersinia pestis / enzymology

Substances

  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Thiophenes
  • thiolactomycin
  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase