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Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase

DOI: 10.1073/pnas.1700721114 DOI Help

Authors: Pan F. Chan (GlaxoSmithKline) , Thomas Germe (John Innes Centre) , Benjamin Bax (GlaxoSmithKline) , Jianzhong Huang (GlaxoSmithKline) , Reema K. Thalji (GlaxoSmithKline) , Eric Bacqué (Sanofi Research & Development) , Anna Checchia (Aptuit Center of Drug Discovery and Development) , Dongzhao Chen (GlaxoSmithKline) , Haifeng Cui (GlaxoSmithKline) , Xiao Ding (GlaxoSmithKline) , Karen Ingraham (GlaxoSmithKline) , Lynn Mccloskey (GlaxoSmithKline) , Kaushik Raha (GlaxoSmithKline) , Velupillai Srikannathasan (GlaxoSmithKline) , Anthony Maxwell (John Innes Centre) , Robert A. Stavenger (GlaxoSmithKline)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 114 , PAGES E4492 - E4500

State: Published (Approved)
Published: May 2017
Diamond Proposal Number(s): 1195

Open Access Open Access

Abstract: A paucity of novel acting antibacterials is in development to treat the rising threat of antimicrobial resistance, particularly in Gram-negative hospital pathogens, which has led to renewed efforts in antibiotic drug discovery. Fluoroquinolones are broad-spectrum antibacterials that target DNA gyrase by stabilizing DNA-cleavage complexes, but their clinical utility has been compromised by resistance. We have identified a class of antibacterial thiophenes that target DNA gyrase with a unique mechanism of action and have activity against a range of bacterial pathogens, including strains resistant to fluoroquinolones. Although fluoroquinolones stabilize double-stranded DNA breaks, the antibacterial thiophenes stabilize gyrase-mediated DNA-cleavage complexes in either one DNA strand or both DNA strands. X-ray crystallography of DNA gyrase–DNA complexes shows the compounds binding to a protein pocket between the winged helix domain and topoisomerase-primase domain, remote from the DNA. Mutations of conserved residues around this pocket affect activity of the thiophene inhibitors, consistent with allosteric inhibition of DNA gyrase. This druggable pocket provides potentially complementary opportunities for targeting bacterial topoisomerases for antibiotic development.

Journal Keywords: antibiotic; topoisomerase; drug discovery

Diamond Keywords: Bacteria

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

Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 12/07/2017 10:24


Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)