title: Discovery of 4-Pyridone derivatives as specific inhibitors of enoyl-acyl carrier protein reductase (FabI) with antibacterial activity against Staphylococcus aureus.
abstract: 4-Pyridone derivatives were identified as potent inhibitors of FabI, the enoyl-acyl carrier protein reductase in Escherichia coli and Staphylococcus aureus. 1-Substituted derivatives of a hit compound exhibited potent antibacterial activities against S. aureus. Target specificity of 4-pyridone derivatives was confirmed by the strong inhibition of lipid synthesis in macromolecular biosynthesis assay and also by the reduced antimicrobial activity against triclosan-resistant S. aureus isolates possessing a point mutation (Ala95Val) in FabI. Two 4-pyridone compounds exhibited strong antibacterial activities against 30 clinical isolates of methicillin-resistant S. aureus (MRSA) with MIC(90) of 0.5 and 2 mug/ml, respectively. Moreover, they retained activity against S. aureus with a mutation affecting FabI residue 204, which was recently found to be associated with triclosan resistance in clinical isolates of S. aureus. In conclusion, we have identified a novel chemical series, 4-pyridone derivatives, as specific inhibitors of FabI with potent antibacterial activity against S. aureus.
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Yokohama, Japan. sho_takahata@meiji.co.jp
authors.forename: Sho
authors.initials: S
authors.lastname: Takahata
authors.forename: Maiko
authors.initials: M
authors.lastname: Iida
authors.forename: Takuji
authors.initials: T
authors.lastname: Yoshida
authors.forename: Ko
authors.initials: K
authors.lastname: Kumura
authors.forename: Hideo
authors.initials: H
authors.lastname: Kitagawa
authors.forename: Shigeru
authors.initials: S
authors.lastname: Hoshiko
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004926:Escherichia coli / Q000235:genetics; D007202:Indicators and Reagents; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D011728:Pyridones / Q000138:chemical synthesis*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics; D014260:Triclosan / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D011728:Pyridones; D014260:Triclosan; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)