Specific inhibition of the eubacterial DNA ligase by arylamino compounds

All known DNA ligases catalyze the formation of a phosphodiester linkage be tween adjacent termini in double-stranded DNA via very similar mechanisms. The ligase family can, however, be divided into two classes: eubacterial li gases, which require NAD(+) as a cofactor, and other ligases, from viruses, archaea, and eukaryotes, which use ATP. Drugs that discriminate between DN A ligases from different sources may have antieubacterial activity. We now report that a group of arylamino compounds, including some commonly used an timalarial and anti-inflammatory drugs and a novel series of bisquinoline c ompounds, are specific inhibitors of eubacterial DNA ligases. Members of th is group of inhibitors have different heterocyclic ring systems with a comm on amino side chain in which the two nitrogens are separated by four carbon atoms. The potency, but not the specificity of action, is influenced by th e DNA-binding characteristics of the inhibitor, and the inhibition is nonco mpetitive with respect to NAD(+). The arylamino compounds appear to target eubacterial DNA ligase in vivo, since a Salmonella Lig(-) strain that has b een rescued with the ATP-dependent T4 DNA ligase is less sensitive than the parental Salmonella strain.