Fragment-based discovery of 6-azaindazoles as inhibitors of bacterial DNA ligase

…, A Hopkins, J Huang, Q Jin, C Kreatsoulas…

Index: Howard, Steven; Amin, Nader; Benowitz, Andrew B.; Chiarparin, Elisabetta; Cui, Haifeng; Deng, Xiaodong; Heightman, Tom D.; Holmes, David J.; Hopkins, Anna; Huang, Jianzhong; Jin, Qi; Kreatsoulas, Constantine; Martin, Agnes C. L.; Massey, Frances; McCloskey, Lynn; Mortenson, Paul N.; Pathuri, Puja; Tisi, Dominic; Williams, Pamela A. ACS Medicinal Chemistry Letters, 2013 , vol. 4, # 12 p. 1208 - 1212

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Citation Number: 9

Abstract

Herein we describe the application of fragment-based drug design to bacterial DNA ligase. X-ray crystallography was used to guide structure-based optimization of a fragment- screening hit to give novel, nanomolar, AMP-competitive inhibitors. The lead compound 13 showed antibacterial activity across a range of pathogens. Data to demonstrate mode of action was provided using a strain of S. aureus, engineered to overexpress DNA ligase.