Mechanism of action of tricyclic drugs on Escherichia coli and Yersinia enterocolitica plasmid maintenance and replication.
Tricyclic medical compounds like many other non-antibiotics exhibit antimicrobial activities. Two chemically representative groups were tested in plasmid DNA transformation and replication to assign intracellular target sites responsible for the multiple effects in Escherichia coli and Yersinia enterocolitica cells. To analyse the mechanism of action at the molecular level, the effects of chlorpromazine, 7,8 dioxochlorpromazine, promethazine, methylene blue, imipramine, cannabidiolic acid and tetrahydrocannabidiolic acid were examined at several points in the course of transformation, in plasmid replication and on the topological state of plasmid DNA. Two possible target sites were identified, one of them involving membrane binding sites which participate in plasmid DNA replication. Drug binding at these sites interfered with the replicating plasmid DNA and membrane protein complex, preventing the proper processing of the replication that resulted in plasmid loss. The other in vivo and in vitro effect was observed on the topological state of plasmid DNA. Tricyclic drugs intefered with energy dependent gyrase activity and promoted the relaxation of plasmid DNA, causing disturbances in gene expression and in plasmid replication. The results give insight into the chemical structures connected with significant specific antimicrobial effects.
Csiszar
K
K
Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814.
Molnar
J
J
D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology; D002746:Chlorpromazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects*; D004269:DNA, Bacterial / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics*; D007099:Imipramine / Q000378:metabolism / Q000494:pharmacology; D008751:Methylene Blue / Q000494:pharmacology; D015394:Molecular Structure; D010957:Plasmids / Q000187:drug effects*; D011398:Promethazine / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014169:Transformation, Bacterial / Q000187:drug effects; D015008:Yersinia enterocolitica / Q000187:drug effects / Q000235:genetics*
D000929:Antidepressive Agents, Tricyclic; D002186:Cannabinoids; D004269:DNA, Bacterial; D011398:Promethazine; D007099:Imipramine; D008751:Methylene Blue; D002746:Chlorpromazine