Discovery of 4-Pyridone derivatives as specific inhibitors of enoyl-acyl carrier protein reductase (FabI) with antibacterial activity against Staphylococcus aureus.
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.
Takahata
Sho
S
Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Yokohama, Japan. sho_takahata@meiji.co.jp
Iida
Maiko
M
Yoshida
Takuji
T
Kumura
Ko
K
Kitagawa
Hideo
H
Hoshiko
Shigeru
S
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
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D011728:Pyridones; D014260:Triclosan; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)