title: Novel E. coli beta-ketoacyl-acyl carrier protein synthase III inhibitors as targeted antibiotics.
abstract: Beta-ketoacyl-acyl carrier protein synthase (KAS) III is a condensing enzyme that initiates fatty acid biosynthesis in most bacteria. We determined three pharmacophore maps from receptor-oriented pharmacophore-based in silico screening of the X-ray structure of Escherichia coli KAS III (ecKAS III) and choose 16 compounds as candidate ecKAS III inhibitors. Binding inhibitors were characterized using saturation-transfer difference NMR spectroscopy (STD-NMR), and binding constants were determined with fluorescence quenching experiments. Based on the results, we propose that the antimicrobial compound, 4-cyclohexyliminomethyl-benzene-1,3-diol (YKAs3003), is a potent inhibitor of pathogenic KAS III, displaying minimal inhibitory concentration (MIC) values in the range 128-256 microg/mL against various bacteria.
authors.affiliation: Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Kwangjin-gu, Seoul, Republic of Korea.
authors.forename: Jee-Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Ki-Woong
authors.initials: KW
authors.lastname: Jeong
authors.forename: Ju-Un
authors.initials: JU
authors.lastname: Lee
authors.forename: Dong-Il
authors.initials: DI
authors.lastname: Kang
authors.forename: Yangmee
authors.initials: Y
authors.lastname: Kim
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001665:Binding Sites; D013293:Enterococcus faecalis / Q000187:drug effects / Q000201:enzymology; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000201:enzymology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D013050:Spectrometry, Fluorescence; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology
chemical_list: D000900:Anti-Bacterial Agents; C077402:3-ketoacyl-acyl carrier protein synthase III; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase