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
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