National Center for
4CC6: Fragment-based Discovery Of 6 Azaindazoles As Inhibitors Of Bacterial Dna Ligase
ACS Med Chem Lett (2013) 4 p.1208-1212
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.