Discovery of Lead Compounds Targeting the Bacterial Sliding Clamp Using a Fragment-Based Approach

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• 作者：Zhou Yin ; Louise R. Whittell ; Yao Wang ; Slobodan Jergic ; Michael Liu ; Elizabeth J. Harry ; Nicholas E. Dixon ; Jennifer L. Beck ; Michael J. Kelso ; Aaron J. Oakley
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 27, 2014
• 年：2014
• 卷：57
• 期：6
• 页码：2799-2806
• 全文大小：479K
• 年卷期：v.57,no.6(March 27, 2014)
• ISSN：1520-4804

文摘

The bacterial sliding clamp (SC), also known as the DNA polymerase III 尾 subunit, is an emerging antibacterial target that plays a central role in DNA replication, serving as a protein鈥損rotein interaction hub with a common binding pocket to recognize linear motifs in the partner proteins. Here, fragment-based screening using X-ray crystallography produced four hits bound in the linear-motif-binding pocket of the Escherichia coli SC. Compounds structurally related to the hits were identified that inhibited the E. coli SC and SC-mediated DNA replication in vitro. A tetrahydrocarbazole derivative emerged as a promising lead whose methyl and ethyl ester prodrug forms showed minimum inhibitory concentrations in the range of 21鈥?3 渭g/mL against representative Gram-negative and Gram-positive bacteria species. The work demonstrates the utility of a fragment-based approach for identifying bacterial sliding clamp inhibitors as lead compounds with broad-spectrum antibacterial activity.