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

Chan Pan F.; Germe Thomas; Bax Benjamin D.Huang JianzhongThalji Reema K.Bacque EricChecchia AnnaChen DongzhaoCui HaifengDing XiaoIngraham KarenMcCloskey LynnRaha KaushikSrikannathasan VelupillaiMaxwell AnthonyStavenger Robert A.

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

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

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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.

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《Proceedings of the National Academy of Sciences of the United States of America.》 |2017年第22期|E4492-E4500|共9页
作者
Chan Pan F.; Germe Thomas; Bax Benjamin D.Huang JianzhongThalji Reema K.Bacque EricChecchia AnnaChen DongzhaoCui HaifengDing XiaoIngraham KarenMcCloskey LynnRaha KaushikSrikannathasan VelupillaiMaxwell AnthonyStavenger Robert A.;
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作者单位

Sanofi Res & Dev, Therapeut Strateg Unit Infect Dis, F-69280 Marcy Letoile, France;

GlaxoSmithKline, Infect Dis Therapy Area Unit, Antibacterial Discovery Performance Unit, Collegeville, PA 19426 USA;

John Innes Ctr, Dept Biol Chem, Norwich Res Pk, Norwich NR4 7UH, Norfolk, EnglandGlaxoSmithKline, Med Res Ctr, Platform Technol & Sci, Stevenage SG1 2NY, Herts, EnglandAptuit Ctr Drug Discovery & Dev, I-37135 Verona, Italy;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
antibiotic; topoisomerase; drug discovery;

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

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