Novel E. coli β-ketoacyl-acyl carrier protein synthase III inhibitors as targeted antibiotics

• Published in: Bioorganic & medicinal chemistry Vol. 17; no. 4; pp. 1506 - 1513
• Main Authors: Lee, Jee-Young, Jeong, Ki-Woong, Lee, Ju-Un, Kang, Dong-Il, Kim, Yangmee
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.02.2009
• Subjects: 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase - antagonists & inhibitors; 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase - genetics; 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase - metabolism; Anti-Bacterial Agents - pharmacology; Antibiotics; Binding Sites; Enterococcus faecalis - drug effects; Enterococcus faecalis - enzymology; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - enzymology; Escherichia coli - genetics; In silico screening; KAS; Klebsiella pneumoniae - drug effects; Klebsiella pneumoniae - enzymology; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - enzymology; Microbial Sensitivity Tests; Models, Molecular; Nuclear Magnetic Resonance, Biomolecular; Spectrometry, Fluorescence; Staphylococcus aureus - drug effects; Staphylococcus aureus - enzymology; STD-NMR; STD-NMR; Antibiotics; In silico screening; KAS
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.01.004

Here, we propose that 4-cyclohexyliminomethyl-benzene-1,3-diol (YKAs3003), is a potent inhibitor of pathogenic KAS III, displaying antibacterial activity against various bacteria. β-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 μg/mL against various bacteria.