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Antimicrobial Agents and Chemotherapy, May 1997, 992-998, Vol 41, No. 5
Copyright © 1997 by the American Society for Microbiology. All rights reserved.

Glycosylated flavones as selective inhibitors of topoisomerase IV

FX Bernard, S Sable, B Cameron, J Provost, JF Desnottes, J Crouzet and F Blanche
Antibacterial Program, Rhone-Poulenc Rorer S.A., Vitry-sur-Seine, France.

Three flavonoids which promoted Escherichia coli topoisomerase IV- dependent DNA cleavage were isolated from cottonseed flour and identified as quercetin 3-O-beta-D-glucose-[1,6]-O-alpha-L-rhamnose (rutin), quercetin 3-O-beta-D-galactose-[1,6]-O-alpha-L-rhamnose, and quercetin 3-O-beta-D-glucose (isoquercitrin). The most active one (rutin) also inhibited topoisomerase IV-dependent decatenation activity (50% inhibitory concentration, 64 microg/ml) and induced the SOS response of a permeable E. coli strain. Derivatives of quercetin glycosylated at position C-3 were shown to induce two site-specific DNA cleavages of pBR322 DNA, which were mapped by DNA sequence analysis to the gene encoding resistance to tetracycline. Cleavage at these sites was hardly detectable in cleavage reactions with quercetin or fluoroquinolones. None of the three flavonoids isolated from cottonseeds had any stimulatory activity on E. coli DNA gyrase- dependent or calf thymus topoisomerase II-dependent DNA cleavage, and they were therefore specific to topoisomerase IV. These results show that selective inhibitors of topoisomerase IV can be derived from the flavone structure. This is the first report on a DNA topoisomerase inhibitor specific for topoisomerase IV.