Back to Search
Start Over
Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2020 Jul 23; Vol. 63 (14), pp. 7773-7816. Date of Electronic Publication: 2020 Jul 07. - Publication Year :
- 2020
-
Abstract
- Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resistance determining region, have eroded the utility and threaten the future use of this vital class of antibiotics. Herein we describe the discovery and optimization of a series of 4-(aminomethyl)quinolin-2(1 H )-ones, exemplified by 34 , that inhibit bacterial DNA gyrase and topoisomerase IV and display potent activity against ciprofloxacin-resistant Gram-negative pathogens. X-ray crystallography reveals that 34 occupies the classical quinolone binding site in the topoisomerase IV-DNA cleavage complex but does not form significant contacts with residues in the quinolone resistance determining region.
- Subjects :
- Anti-Bacterial Agents chemical synthesis
Anti-Bacterial Agents metabolism
Anti-Bacterial Agents toxicity
Binding Sites
Cell Line, Tumor
DNA Gyrase metabolism
DNA Topoisomerase IV antagonists & inhibitors
DNA Topoisomerase IV chemistry
Fluoroquinolones chemical synthesis
Fluoroquinolones metabolism
Fluoroquinolones toxicity
Gram-Negative Bacteria enzymology
Humans
Microbial Sensitivity Tests
Molecular Structure
Structure-Activity Relationship
Topoisomerase II Inhibitors chemical synthesis
Topoisomerase II Inhibitors metabolism
Topoisomerase II Inhibitors toxicity
Anti-Bacterial Agents pharmacology
Drug Resistance, Bacterial drug effects
Fluoroquinolones pharmacology
Gram-Negative Bacteria drug effects
Topoisomerase II Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 63
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 32634310
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.0c00347