Specific Inhibition of the Eubacterial DNA Ligase by Arylamino Compounds Academic Article uri icon

abstract

  • All known DNA ligases catalyze the formation of a phosphodiester linkage between adjacent termini in double-stranded DNA via very similar mechanisms. The ligase family can, however, be divided into two classes: eubacterial ligases, which require NAD+ as a cofactor, and other ligases, from viruses, archaea, and eukaryotes, which use ATP. Drugs that discriminate between DNA ligases from different sources may have antieubacterial activity. We now report that a group of arylamino compounds, including some commonly used antimalarial and anti-inflammatory drugs and a novel series of bisquinoline compounds, are specific inhibitors of eubacterial DNA ligases. Members of this group of inhibitors have different heterocyclic ring systems with a common 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 the DNA-binding characteristics of the inhibitor, and the inhibition is noncompetitive with respect to NAD+. The arylamino compounds appear to target eubacterial DNA ligase in vivo, since a SalmonellaLig strain that has been rescued with the ATP-dependent T4 DNA ligase is less sensitive than the parentalSalmonella strain.

authors

  • Ciarrocchi, Giovanni
  • MacPhee, Donald G
  • Deady, Les W
  • Tilley, Leann

publication date

  • November 1, 1999