Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase
| Autor: | Thomas Germe, Eric Bacqué, Lynn McCloskey, Kaushik Raha, Haifeng Cui, Anthony Maxwell, Benjamin D. Bax, Reema K. Thalji, Anna Checchia, Dongzhao Chen, Pan F. Chan, Jianzhong Huang, Xiao Ding, Robert A. Stavenger, Velupillai Srikannathasan, Karen A. Ingraham |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Models Molecular Stereochemistry 030106 microbiology Allosteric regulation Druggability Thiophenes Winged Helix Crystallography X-Ray DNA gyrase 03 medical and health sciences chemistry.chemical_compound Antibiotic resistance Drug Discovery DNA Cleavage Multidisciplinary biology Drug discovery Topoisomerase Anti-Bacterial Agents 030104 developmental biology chemistry Biochemistry PNAS Plus DNA Gyrase biology.protein DNA |
| ISSN: | 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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