Structure-Based Design of Potent and Ligand-Efficient Inhibitors of CTX-M Class A 尾-Lactamase

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• 作者：Derek A. Nichols ; Priyadarshini Jaishankar ; Wayne Larson ; Emmanuel Smith ; Guoqing Liu ; Racha Beyrouthy ; Richard Bonnet ; Adam R. Renslo ; Yu Chen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：March 8, 2012
• 年：2012
• 卷：55
• 期：5
• 页码：2163-2172
• 全文大小：422K
• 年卷期：v.55,no.5(March 8, 2012)
• ISSN：1520-4804

文摘

The emergence of CTX-M class A extended-spectrum 尾-lactamases poses a serious health threat to the public. We have applied structure-based design to improve the potency of a novel noncovalent tetrazole-containing CTX-M inhibitor (K_i = 21 渭M) more than 200-fold via structural modifications targeting two binding hot spots, a hydrophobic shelf formed by Pro167 and a polar site anchored by Asp240. Functional groups contacting each binding hot spot independently in initial designs were later combined to produce analogues with submicromolar potencies, including 6-trifluoromethyl-3H-benzoimidazole-4-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]-amide, which had a K_i value of 89 nM and reduced the MIC of cefotaxime by 64-fold in CTX-M-9 expressing Escherichia coli. The in vitro potency gains were accompanied by improvements in ligand efficiency (from 0.30 to 0.39) and LipE (from 1.37 to 3.86). These new analogues represent the first nM-affinity noncovalent inhibitors of a class A 尾-lactamase. Their complex crystal structures provide valuable information about ligand binding for future inhibitor design.