title: Thiolactomycin-Based Inhibitors of Bacterial β-Ketoacyl-ACP Synthases with in Vivo Activity.
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.
authors.forename: Gopal R
authors.initials: GR
authors.lastname: Bommineni
authors.forename: Kanishk
authors.initials: K
authors.lastname: Kapilashrami
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, Colorado 80523-2025, United States.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Cummings
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, Colorado 80523-2025, United States.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Knudson
authors.forename: Chendi
authors.initials: C
authors.lastname: Gu
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Walker
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, Colorado 80523-2025, United States.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Slayden
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tonge
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016957:Burkholderia pseudomallei / Q000187:drug effects / Q000201:enzymology; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005604:Francisella tularensis / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007710:Klebsiella Infections / Q000188:drug therapy; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000201:enzymology; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015010:Yersinia pestis / Q000187:drug effects / Q000201:enzymology
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D013876:Thiophenes; C035068:thiolactomycin; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase