PMID:7811004
| Citation |
Nakada, N, Gmünder, H, Hirata, T and Arisawa, M (1994) Mechanism of inhibition of DNA gyrase by cyclothialidine, a novel DNA gyrase inhibitor. Antimicrob. Agents Chemother. 38:1966-73 |
|---|---|
| Abstract |
We investigated how cyclothialidine (Ro 09-1437), a novel DNA gyrase inhibitor belonging to a new chemical class of compounds, acts to inhibit Escherichia coli DNA gyrase. Cyclothialidine up to 100 micrograms/ml showed no effect on DNA gyrase when linear DNA was used as a substrate. Under the same conditions, quinolones, which inhibit the resealing reaction of DNA gyrase, caused a decrease in the amount of linear DNA used. No effect of cyclothialidine was observed on the accumulation of the covalent complex of DNA and the A subunit of DNA gyrase induced by ofloxacin in the absence of ATP. The effect of cyclothialidine on the DNA supercoiling reaction was antagonized by ATP, reducing the inhibitory activity 11-fold as the ATP concentration was increased from 0.5 to 5 mM. Cyclothialidine competitively inhibited the ATPase activity of DNA gyrase (Ki = 6 nM). The binding of [14C]benzoyl-cyclothialidine to E. coli gyrase was inhibited by ATP and novobiocin, but not by ofloxacin. These results suggest that cyclothialidine acts by interfering with the ATPase activity of the B subunit of DNA gyrase. Cyclothialidine was active against a DNA gyrase resistant to novobiocin, suggesting that its precise site of action might be different from that of novobiocin. |
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| Keywords |
4-Quinolones; Adenosine Triphosphatases/antagonists & inhibitors; Adenosine Triphosphate/metabolism; Adenosine Triphosphate/pharmacology; Anti-Bacterial Agents/pharmacology; Anti-Infective Agents/pharmacology; Binding, Competitive; Carbon Radioisotopes; Coumarins/pharmacology; DNA Topoisomerases, Type II/genetics; DNA Topoisomerases, Type II/metabolism; DNA, Bacterial/drug effects; DNA, Bacterial/metabolism; DNA, Superhelical/drug effects; DNA, Superhelical/metabolism; Escherichia coli/enzymology; Escherichia coli/genetics; Mutation; Peptides, Cyclic/antagonists & inhibitors; Peptides, Cyclic/metabolism; Peptides, Cyclic/pharmacology; Topoisomerase II Inhibitors |
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