Discovery of novel selective inhibitors of Staphylococcus aureus ¦Â-ketoacyl acyl carrier protein synthase III

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• 作者：Jee-Young Lee ; Ki-Woong Jeong ; Soyoung Shin ; Ju-Un Lee ; Yangmee Kim ; ^{ymkim@konkuk.ac.kr}
• 关键词：KAS ; Fatty acid synthesis ; Antibiotics ; In silico screening ; MRSA
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：January, 2012
• 年：2012
• 卷：47
• 期：Complete
• 页码：261-269
• 全文大小：768 K

文摘

¦Â-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?¦Ìg/mL.