Type IIA topoisomerase inhibition by a new class of antibacterial agents
Autor: | Benjamin D. Bax, Pan F. Chan, Michael M. Hann, Michael N. Gwynn, Daniel R. Gentry, Ceri J. Lewis, Jo J. Jones, Claus Spitzfaden, Andrew P. Fosberry, Martin Hibbs, Earl May, Kristin K. Brown, Alexandre Wohlkonig, Drake S. Eggleston, Onkar M. P. Singh, Alan Joseph Hennessy, Andrew J. Theobald, Fabrice Gorrec, Martin R. Saunders, Anthony Shillings, Emma J. Jones, Carol Shen, Neil D. Pearson, Jianzhong Huang, Ilaria Giordano |
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Přispěvatelé: | Department of Bio-engineering Sciences, Structural Biology Brussels |
Jazyk: | angličtina |
Rok vydání: | 2010 |
Předmět: |
Models
Molecular Gepotidacin Staphylococcus aureus Stereochemistry Protein Conformation Drug Resistance Anti-Bacterial Agents/chemistry Quinolones Manganese/metabolism Arginine Crystallography X-Ray DNA gyrase Apoenzymes Arginine/metabolism Ciprofloxacin Catalytic Domain Escherichia coli Topoisomerase II Inhibitors Ciprofloxacin/chemistry DNA Gyrase/chemistry DNA Superhelical/chemistry Escherichia coli/enzymology DNA Cleavage DNA/chemistry Quinolines/chemistry Antibacterial agent Aspartic Acid Manganese Multidisciplinary Binding Sites biology Apoenzymes/chemistry Drug discovery DNA Superhelical Topoisomerase DNA Staphylococcus aureus/enzymology Structure-activity relationship Quinolones/chemistry Anti-Bacterial Agents Biochemistry DNA Gyrase Drug Design biology.protein Quinolines Primase Topoisomerase-II Inhibitor Type II topoisomerase Aspartic Acid/metabolism |
DOI: | 10.1038/nature09197 |
Popis: | Despite the success of genomics in identifying new essential bacterial genes, there is a lack of sustainable leads in antibacterial drug discovery to address increasing multidrug resistance. Type IIA topoisomerases cleave and religate DNA to regulate DNA topology and are a major class of antibacterial and anticancer drug targets, yet there is no well developed structural basis for understanding drug action. Here we report the 2.1 A crystal structure of a potent, new class, broad-spectrum antibacterial agent in complex with Staphylococcus aureus DNA gyrase and DNA, showing a new mode of inhibition that circumvents fluoroquinolone resistance in this clinically important drug target. The inhibitor 'bridges' the DNA and a transient non-catalytic pocket on the two-fold axis at the GyrA dimer interface, and is close to the active sites and fluoroquinolone binding sites. In the inhibitor complex the active site seems poised to cleave the DNA, with a single metal ion observed between the TOPRIM (topoisomerase/primase) domain and the scissile phosphate. This work provides new insights into the mechanism of topoisomerase action and a platform for structure-based drug design of a new class of antibacterial agents against a clinically proven, but conformationally flexible, enzyme class. |
Databáze: | OpenAIRE |
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