Structure-guided design of antibacterials that allosterically inhibit DNA gyrase

Autor:	Pan F. Chan, Kaushik Raha, Shruti Jain, Geoffrey Quinque, Margarete Neu, Daniele Andreotti, Roberto Profeta, Reema K. Thalji, Brian Donovan, Simona Tommasi, Lynn McCloskey, Christopher J. Nixon, Giovanni Meneghelli, Tania Bakshi, Anna Checchia, Robert A. Stavenger, Benjamin D. Bax, Alison Howells, Federica Tonelli, Haifeng Cui
Rok vydání:	2019
Předmět:	Acinetobacter baumannii Models Molecular medicine.drug_class Clinical Biochemistry Antibiotics Pharmaceutical Science Microbial Sensitivity Tests Isomerase Crystallography X-Ray 01 natural sciences Biochemistry DNA gyrase Cell Line Mice Structure-Activity Relationship Drug Discovery Escherichia coli medicine Animals Humans Topoisomerase II Inhibitors Molecular Biology Ion channel Mice Knockout Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Chemistry Topoisomerase Organic Chemistry Biochemical Activity Anti-Bacterial Agents 0104 chemical sciences 010404 medicinal & biomolecular chemistry Ion channel activity DNA Gyrase Drug Design biology.protein Molecular Medicine Antibacterial activity
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 29:1407-1412
ISSN:	0960-894X
Popis:	A series of DNA gyrase inhibitors were designed based on the X-ray structure of a parent thiophene scaffold with the objective to improve biochemical and whole-cell antibacterial activity, while reducing cardiac ion channel activity. The binding mode and overall design hypothesis of one series was confirmed with a co-crystal structure with DNA gyrase. Although some analogs retained both biochemical activity and whole-cell antibacterial activity, we were unable to significantly improve the activity of the series and analogs retained activity against the cardiac ion channels, therefore we stopped optimization efforts.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f63ff5d1f9eeb44a22b39b1dba435047 https://doi.org/10.1016/j.bmcl.2019.03.029 Zobrazit plný text záznamu Full Text from ScienceDirect