title: Discovery of novel selective inhibitors of Staphylococcus aureus β-ketoacyl acyl carrier protein synthase III.
abstract: β-Ketoacyl-acyl carrier protein synthase III (KAS III) is a condensing enzyme in bacterial fatty acid synthesis and a potential target while designing novel antibiotics. In our previous report, we discovered the lead compound YKAs3003, which serves as an inhibitor of Escherichia coli KAS III (ecKAS III), and determined a reliable pharmacophore map from in silico screening. In this study, we determined two pharmacophore maps from receptor-oriented pharmacophore-based in silico screening of the x-ray structure of Staphylococcus aureus KAS III (saKAS III) to identify potent saKAS III inhibitors. We discovered a new potential inhibitor (6) with broad-spectrum antimicrobial activity and 0.8 nM binding affinity for saKAS III, proving the reliability of our pharmacophore map. Using optimization procedures, we identified three new antimicrobial saKAS III inhibitors: 6c (2,4-dichloro-benzoic acid (2,3,4-trihydroxy-benzylidene)-hydrazide), 6e (4-[(3-chloro-pyrazin-2-yl)-hydrazonomethyl]-benzene-1,3-diol), and 6 (4-[(5-trifluoromethyl-pyridin-2-yl)-hydrazonomethyl]-benzene-1,3-diol). All three inhibitors have a novel 4-hydrazonomethyl-benzene-1,3-diol core structure. These inhibitors exhibited high binding affinity to saKAS III and highly selective antimicrobial activities against S. aureus and methicillin-resistant S. aureus, with minimal inhibitory concentration values of 1-2 μg/mL.
authors: Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, South Korea.
authors: Jee-Young
authors: JY
authors: Lee
authors: Ki-Woong
authors: KW
authors: Jeong
authors: Soyoung
authors: S
authors: Shin
authors: Ju-Un
authors: JU
authors: Lee
authors: Yangmee
authors: Y
authors: Kim
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D000890:Anti-Infective Agents / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008958:Models, Molecular; D041681:NIH 3T3 Cells; D011487:Protein Conformation; D013050:Spectrometry, Fluorescence; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology*; D013379:Substrate Specificity
chemical_list: D000890:Anti-Infective Agents; D004791:Enzyme Inhibitors; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase