Unique Biological Properties and Molecular Mechanism of 5,6-Bridged Quinolones
| Autor: | Min Li, Kelly M. Makin, David H. Ellis, Erica Marie Kincaid, Allison A. Kreiner, Paul J. Renick, Benoit Ledoussal, Cynthia D. Wallace, Timothy W. Morris, David R. Macinga, Kirk J. Rupnik |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Bridged-Ring Compounds
Genotype Nalidixic acid Topoisomerase Inhibitors medicine.drug_class Stereochemistry Oligonucleotides Microbial Sensitivity Tests Biology medicine.disease_cause DNA gyrase Structure-Activity Relationship chemistry.chemical_compound Anti-Infective Agents Escherichia coli medicine Topoisomerase II Inhibitors Pharmacology (medical) Enzyme Inhibitors Mechanisms of Action: Physiological Effects Pharmacology Mutation 4-Quinolones DNA Superhelical Quinolone Kinetics Phenotype Infectious Diseases Biochemistry chemistry DNA Gyrase DNA supercoil Clinafloxacin Topoisomerase inhibitor Bacterial Outer Membrane Proteins medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 47:2526-2537 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.47.8.2526-2537.2003 |
| Popis: | We have characterized an early series of 5,6-bridged dioxinoquinolones which behaved strikingly different from typical quinolones. The 5,6-bridged dioxinoquinolones inhibited Escherichia coli DNA gyrase supercoiling activity but, unlike typical quinolones, failed to stimulate gyrase-dependent cleavable complex formation. Analogous unsubstituted compounds stimulated cleavable complex formation but were considerably less potent than the corresponding 5,6-bridged compounds. Consistent with a previous report (M. Antoine et al., Chim. Ther. 7:434-443, 1972) and contrary to established quinolone SAR trends, a compound with an N-1 methyl substitution (PGE-8367769) was more potent than its analog with an N-1 ethyl substitution (PGE-6596491). PGE-8367769 was shown to antagonize ciprofloxacin-mediated cleavable complex formation in a dose-dependent manner, suggesting an interaction with the gyrase-DNA complex that overlaps that of ciprofloxacin. Resistance to PGE-8367769 in E. coli was found to arise through missense mutations in gyrA , implicating DNA gyrase as the primary antibacterial target. Notably, only 1 of 15 distinct mutations selected on PGE-8367769 (D87G) has previously been implicated in quinolone resistance in E. coli. The remaining 14 mutations (E16V, G31V, R38L, G40A, Y50D, V70A, A84V, I89L, M135T, G173S, T180I, F217C, P218T, and F513C) have not been previously reported, and most were located outside of the traditional quinolone resistance-determining region. These novel GyrA mutations decreased sensitivity to 5,6-bridged dioxinoquinolones by four- to eightfold, whereas they did not confer resistance to other quinolones such as ciprofloxacin, clinafloxacin, or nalidixic acid. These results demonstrate that the 5,6-bridged quinolones act via a mechanism that is related to but qualitatively different from that of typical quinolones. |
| Databáze: | OpenAIRE |
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