Article Metrics


Online attention

Structure-guided design of antibacterials that allosterically inhibit DNA gyrase

DOI: 10.1016/j.bmcl.2019.03.029 DOI Help

Authors: Reema K. Thalji (GlaxoSmithKline) , Kaushik Raha (GlaxoSmithKline) , Daniele Andreotti (EVOTEC Center of Drug Discovery and Development) , Anna Checchia (EVOTEC Center of Drug Discovery and Development) , Haifeng Cui (GlaxoSmithKline) , Giovanni Meneghelli (EVOTEC Center of Drug Discovery and Development) , Roberto Profeta (EVOTEC Center of Drug Discovery and Development) , Federica Tonelli (EVOTEC Center of Drug Discovery and Development) , Simona Tommasi (EVOTEC Center of Drug Discovery and Development) , Tania Bakshi (GlaxoSmithKline) , Brian T. Donovan (GlaxoSmithKline) , Alison Howells (Inspiralis Ltd. Innovation Centre) , Shruti Jain (Inspiralis Ltd. Innovation Centre) , Christopher Nixon (GlaxoSmithKline) , Geoffrey Quinque (GlaxoSmithKline) , Lynn Mccloskey (GlaxoSmithKline) , Benjamin D. Bax (GlaxoSmithKline) , Margarete Neu (GlaxoSmithKline) , Pan F. Chan (GlaxoSmithKline) , Robert A. Stavenger (GlaxoSmithKline)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry Letters

State: Published (Approved)
Published: March 2019
Diamond Proposal Number(s): 1195

Abstract: 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.

Journal Keywords: Antibacterial; Topoisomerase

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Medicine, Chemistry

Instruments: I03-Macromolecular Crystallography , I23-Long wavelength MX

Added On: 17/04/2019 08:44

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Antibiotic Resistance Drug Discovery Infectious Diseases Pathogens Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Long Wavelength Crystallography