Compounds with antibacterial activity that enhance DNA cleavage by bacterial DNA topoisomerase I.
OBJECTIVE
DNA topoisomerases utilize a covalent complex formed after DNA cleavage as an intermediate in the interconversion of topological forms via DNA cleavage and religation. Many anticancer and antibacterial therapeutic agents are effective because they stabilize or increase the level of the covalent topoisomerase-DNA complex formed by type IIA or type IB topoisomerases. Our goal is to identify small molecules that can enhance DNA cleavage by type IA DNA topoisomerase. Compounds that act in this mechanism against type IA topoisomerase have not been identified previously and could be leads for development of a new class of antibacterial agents.


METHODS
High throughput screening was carried out to select small molecules that induce the SOS response of Escherichia coli, overexpressing recombinant Yersinia pestis topoisomerase I. The initial hit compounds were further tested for inhibition of bacterial growth and bacterial topoisomerase I activity.


RESULTS
Three compounds with antibacterial activity that enhance the cleavage activity of bacterial topoisomerase I were identified.


CONCLUSIONS
Small molecules that can enhance the DNA cleavage activity of type IA DNA topoisomerase can be identified and may provide leads for development of novel antibacterial compounds.
Cheng
Bokun
B
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA.
Liu
I-Fen
IF
Tse-Dinh
Yuk-Ching
YC
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects / Q000235:genetics; D004269:DNA, Bacterial / Q000187:drug effects; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D008156:Luciferases / Q000096:biosynthesis / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D059004:Topoisomerase I Inhibitors; D014615:Vaccinia / Q000201:enzymology; D015010:Yersinia pestis / Q000187:drug effects / Q000201:enzymology
D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D008156:Luciferases