Mechanism of inhibition of DNA gyrase by ES-1273, a novel DNA gyrase inhibitor.
We investigated the mode of action of ES-1273, a novel DNA gyrase inhibitor obtained by optimization of ES-0615, which was found by screening our chemical library using anucleate cell blue assay. ES-1273 exhibited the same antibacterial activity against S. aureus strains with amino acid change(s) conferring quinolone- and coumarin-resistance as that against a susceptible strain. In addition, ES-1273 inhibited DNA gyrase supercoiling activity, but not ATPase activity of the GyrB subunit of DNA gyrase. Moreover, ES-1273 did not induce cleavable complex. These findings demonstrate that the mechanism by which ES-1273 inhibits DNA gyrase is different from that of the quinolones or the coumarins. Preincubation of DNA gyrase and substrate DNA prevented inhibition of DNA gyrase supercoiling activity by ES-1273. ES-1273 antagonized quinolone-induced cleavage. In electrophoretic mobility shift assay, no band representing DNA gyrase-DNA complex was observed in the presence of ES-1273. Taken together, these results indicate that ES-1273 prevents DNA from binding to DNA gyrase. Furthermore, our results from surface plasmon resonance experiments strongly suggest that ES-1273 interacts with DNA. Therefore, the interaction between ES-1273 and DNA prevents DNA from binding to DNA gyrase, resulting in inhibition of DNA gyrase supercoiling. Interestingly, we also found that ES-1273 inhibits topoisomerase IV and human topoisomerase IIalpha, but not human topoisomerase I. These findings indicate that ES-1273 is a type II topoisomerase specific inhibitor.
Oyamada
Yoshihiro
Y
Pharmacology Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd, suita, Osaka 564-0053, Japan.
Yamagishi
Jun-ichi
J
Kihara
Takahiro
T
Yoshida
Hiroaki
H
Wachi
Masaaki
M
Ito
Hideaki
H
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004269:DNA, Bacterial / Q000378:metabolism; D004278:DNA, Superhelical / Q000037:antagonists & inhibitors / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology; D006095:Gram-Positive Cocci / Q000187:drug effects* / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology; D059005:Topoisomerase II Inhibitors
D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D004278:DNA, Superhelical; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D059005:Topoisomerase II Inhibitors