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Mechanism of inhibition of DNA gyrase by ES-1273, a novel DNA gyrase inhibitor.
- Source :
-
Microbiology and immunology [Microbiol Immunol] 2007; Vol. 51 (10), pp. 977-84. - Publication Year :
- 2007
-
Abstract
- 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.
- Subjects :
- DNA, Bacterial metabolism
DNA, Superhelical antagonists & inhibitors
DNA, Superhelical metabolism
Drug Resistance, Bacterial
Enzyme Inhibitors chemistry
Escherichia coli enzymology
Gram-Positive Cocci enzymology
Microbial Sensitivity Tests
Staphylococcus aureus enzymology
Anti-Bacterial Agents pharmacology
Enzyme Inhibitors pharmacology
Escherichia coli drug effects
Gram-Positive Cocci drug effects
Pyrazoles chemistry
Pyrazoles pharmacology
Staphylococcus aureus drug effects
Topoisomerase II Inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0385-5600
- Volume :
- 51
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Microbiology and immunology
- Publication Type :
- Academic Journal
- Accession number :
- 17951987
- Full Text :
- https://doi.org/10.1111/j.1348-0421.2007.tb03994.x