Specific inhibition of the eubacterial DNA ligase by arylamino compounds.
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.
Ciarrocchi
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G
Istituto di Genetica Biochimica ed Evoluzionistica, CNR, Pavia 27100, Italy. gcia@bioserve.latrobe.edu.au
MacPhee
D G
DG
Deady
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Tilley
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D000255:Adenosine Triphosphate / Q000502:physiology; D000631:Aminopyridines / Q000494:pharmacology*; D000814:Aniline Compounds / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D011088:DNA Ligases; D004269:DNA, Bacterial / Q000302:isolation & purification / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D006863:Hydrogen-Ion Concentration; D008025:Ligases / Q000037:antagonists & inhibitors / Q000302:isolation & purification*; D009243:NAD / Q000502:physiology; D012486:Salmonella typhimurium / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development
D000631:Aminopyridines; D000814:Aniline Compounds; D000903:Antibiotics, Antineoplastic; D004269:DNA, Bacterial; D004791:Enzyme Inhibitors; D009243:NAD; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D008025:Ligases; D011088:DNA Ligases; C120640:DNA ligase (NAD)