From Fragments to Leads: Novel Bacterial Nad+-Dependent DNA Ligase Inhibitors

Abstract 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.