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Discovery and Optimization of DNA Gyrase and Topoisomerase IV Inhibitors with Potent Activity against Fluoroquinolone-Resistant Gram-Positive Bacteria.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2021 May 13; Vol. 64 (9), pp. 6329-6357. Date of Electronic Publication: 2021 Apr 30. - Publication Year :
- 2021
-
Abstract
- Herein, we describe the discovery and optimization of a novel series that inhibits bacterial DNA gyrase and topoisomerase IV via binding to, and stabilization of, DNA cleavage complexes. Optimization of this series led to the identification of compound 25 , which has potent activity against Gram-positive bacteria, a favorable in vitro safety profile, and excellent in vivo pharmacokinetic properties. Compound 25 was found to be efficacious against fluoroquinolone-sensitive Staphylococcus aureus infection in a mouse thigh model at lower doses than moxifloxacin. An X-ray crystal structure of the ternary complex formed by topoisomerase IV from Klebsiella pneumoniae , compound 25 , and cleaved DNA indicates that this compound does not engage in a water-metal ion bridge interaction and forms no direct contacts with residues in the quinolone resistance determining region (QRDR). This suggests a structural basis for the reduced impact of QRDR mutations on antibacterial activity of 25 compared to fluoroquinolones.
- Subjects :
- Animals
Anti-Bacterial Agents chemistry
Drug Resistance, Bacterial drug effects
Mice
Topoisomerase II Inhibitors chemistry
Anti-Bacterial Agents pharmacology
DNA Gyrase metabolism
DNA Topoisomerase IV antagonists & inhibitors
Drug Design
Fluoroquinolones pharmacology
Staphylococcus aureus drug effects
Topoisomerase II Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 64
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33929852
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.1c00375