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Antimicrobial Agents and Chemotherapy, November 1999, p. 2766-2772, Vol. 43, No. 11
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Specific Inhibition of the Eubacterial DNA Ligase by Arylamino Compounds

Giovanni Ciarrocchi,1,* Donald G. MacPhee,2 Les W. Deady,3 and Leann Tilley4

Istituto di Genetica Biochimica ed Evoluzionistica, CNR, Pavia 27100, Italy,1 and Departments of Microbiology,2 Chemistry,3 and Biochemistry,4 La Trobe University, Bundoora, Victoria 3083, Australia

Received 6 May 1999/Returned for modification 10 August 1999/Accepted 4 September 1999

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 Salmonella Lig- strain that has been rescued with the ATP-dependent T4 DNA ligase is less sensitive than the parental Salmonella strain.

* Corresponding author. Present address: Department of Biochemistry, La Trobe University, Bundoora, Victoria 3083, Australia. Phone: 61 3 9479 3044. Fax: 61 3 9479 2467. E-mail: gcia{at}bioserve.latrobe.edu.au.

Antimicrobial Agents and Chemotherapy, November 1999, p. 2766-2772, Vol. 43, No. 11
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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