title: Allosteric inhibition of the DNA-dependent ATPase activity of Escherichia coli DNA gyrase by a representative of a novel class of inhibitors.
abstract: A novel class of bacterial DNA gyrase inhibitors has been shown previously to form a ternary complex with DNA and gyrase in a site distinct from the fluoroquinolone and ATP binding sites and does not cause double-strand-cleaved complex stabilization like fluoroquinolones. We show that, unlike fluoroquinolones, a representative compound inhibits DNA-dependent ATP hydrolysis by Escherichia coli gyrase and also blocks cleaved complex stabilization by ciprofloxacin. Conversely, ciprofloxacin blocks ATPase inhibition by the novel compound. We conclude that the compound acts allosterically to inhibit ATP binding or hydrolysis and interferes with the gyrase catalytic cycle at a different point than ciprofloxacin.
authors: Bioscience Department, Infection Innovative Medicines, AstraZeneca R&D Boston, Waltham, MA 02451, USA. adam.shapiro@astrazeneca.com
authors: Adam B
authors: AB
authors: Shapiro
authors: Beth
authors: B
authors: Andrews
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000494:Allosteric Regulation / Q000187:drug effects; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001665:Binding Sites; D002939:Ciprofloxacin / Q000494:pharmacology; D027081:DNA Gyrase / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D002939:Ciprofloxacin; D000251:Adenosine Triphosphatases; D027081:DNA Gyrase