From fragments to leads: novel bacterial NAD+-dependent DNA ligase inhibitors

Bacterial NAD(+)-dependent DNA ligase (LigA) is an essential enzyme involved in the repair, replication, and recombination of DNA in all bacteria, making it an attractive target in antibacterial drug discovery. A novel series of LigA inhibitors was discovered by combining information from fragment-based lead generation, X-ray crystal structures of previously discovered inhibitors bound to the adenosine binding site of LigA bound to and established structure-activity relationships of LigA inhibitors. The compounds described here were evaluated in a variety of Gram-positive and Gram-negative pathogens as well as evaluation of physical properties. (C) 2014 Elsevier Ltd. All rights reserved.