5NPP

2.22A STRUCTURE OF THIOPHENE2 AND GSK945237 WITH S.AUREUS DNA GYRASE AND DNA

Summary for 5NPP

• Entry DOI: 10.2210/pdb5npp/pdb
• Descriptor: DNA gyrase subunit B,DNA gyrase subunit B,DNA gyrase subunit A, DNA (5'-D(*AP*GP*CP*CP*GP*TP*AP*GP*GP*TP*AP*CP*CP*TP*AP*CP*GP*GP*CP*T)-3'), MANGANESE (II) ION, ... (10 entities in total)
• Functional Keywords: type iia topoisomerase, antibacterial, inhibitor, isomerase
• Biological source: Staphylococcus aureus; More
• Cellular location: Cytoplasm : Q99XG5
• Total number of polymer chains: 6
• Total formula weight: 170663.15

Authors

Bax, B.D.,Chan, P.F.,Stavenger, R.A. (deposition date: 2017-04-18, release date: 2017-07-12, Last modification date: 2024-05-08)

Primary citation

Chan, P.F.,Germe, T.,Bax, B.D.,Huang, J.,Thalji, R.K.,Bacque, E.,Checchia, A.,Chen, D.,Cui, H.,Ding, X.,Ingraham, K.,McCloskey, L.,Raha, K.,Srikannathasan, V.,Maxwell, A.,Stavenger, R.A.
Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase.
Proc. Natl. Acad. Sci. U.S.A., 114:E4492-E4500, 2017

PubMed 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.

PubMed: 28507124
DOI: 10.1073/pnas.1700721114

Experimental method

X-RAY DIFFRACTION (2.22 Å)