Type IIA topoisomerase inhibition by a new class of antibacterial agents

Benjamin D. Bax (), Pan F. Chan, Drake S. Eggleston, Andrew Fosberry, Daniel R. Gentry, Fabrice Gorrec, Ilaria Giordano, Michael M. Hann, Alan Hennessy, Martin Hibbs, Jianzhong Huang, Emma Jones, Jo Jones, Kristin Koretke Brown, Ceri J. Lewis, Earl W. May, Martin R. Saunders, Onkar Singh, Claus E. Spitzfaden, Carol Shen, Anthony Shillings, Andrew J. Theobald, Alexandre Wohlkonig, Neil D. Pearson and Michael N. Gwynn ()
Additional contact information
Benjamin D. Bax: Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
Pan F. Chan: Antibacterial Discovery Performance Unit, Infectious Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline
Drake S. Eggleston: Molecular Discovery Research, GlaxoSmithKline, Third Ave, Harlow, Essex, CM19 5AW, UK
Andrew Fosberry: Molecular Discovery Research, GlaxoSmithKline, Third Ave, Harlow, Essex, CM19 5AW, UK
Daniel R. Gentry: Antibacterial Discovery Performance Unit, Infectious Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline
Fabrice Gorrec: Molecular Discovery Research, GlaxoSmithKline, Third Ave, Harlow, Essex, CM19 5AW, UK
Ilaria Giordano: Antibacterial Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
Michael M. Hann: Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
Alan Hennessy: Antibacterial Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
Martin Hibbs: Molecular Discovery Research, GlaxoSmithKline, Third Ave, Harlow, Essex, CM19 5AW, UK
Jianzhong Huang: Antibacterial Discovery Performance Unit, Infectious Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline
Emma Jones: Molecular Discovery Research, GlaxoSmithKline, Third Ave, Harlow, Essex, CM19 5AW, UK
Jo Jones: Molecular Discovery Research, GlaxoSmithKline, Third Ave, Harlow, Essex, CM19 5AW, UK
Kristin Koretke Brown: Molecular Discovery Research, GlaxoSmithKline
Ceri J. Lewis: Molecular Discovery Research, GlaxoSmithKline, Third Ave, Harlow, Essex, CM19 5AW, UK
Earl W. May: Antibacterial Discovery Performance Unit, Infectious Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline
Martin R. Saunders: Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
Onkar Singh: Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
Claus E. Spitzfaden: Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
Carol Shen: Antibacterial Discovery Performance Unit, Infectious Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline
Anthony Shillings: Molecular Discovery Research, GlaxoSmithKline, Third Ave, Harlow, Essex, CM19 5AW, UK
Andrew J. Theobald: Molecular Discovery Research, GlaxoSmithKline, Third Ave, Harlow, Essex, CM19 5AW, UK
Alexandre Wohlkonig: Antibacterial Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
Neil D. Pearson: Antibacterial Discovery Performance Unit, Infectious Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline
Michael N. Gwynn: Antibacterial Discovery Performance Unit, Infectious Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline

Nature, 2010, vol. 466, issue 7309, 935-940

Abstract: Abstract 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 Å 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.

Date: 2010
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DOI: 10.1038/nature09197

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