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Nature. Type IIA topoisomerase inhibition by a new class of antibacterial agents
Type IIA topoisomerase inhibition by a new class of antibacterial agents (Nature, abstract, edited)
[Source: Nature, <cite cite="http://www.nature.com/nature/journal/v466/n7309/full/nature09197.html">Access : Type IIA topoisomerase inhibition by a new class of antibacterial agents : Nature</cite>. Abstract, edited.]
Nature 466, 935-940 (19 August 2010) | doi:10.1038/nature09197; Received 11 October 2009; Accepted 20 May 2010; Published online 4 August 2010; Corrected 19 August 2010
Type IIA topoisomerase inhibition by a new class of antibacterial agents
Benjamin D. Bax 1, Pan F. Chan 2, Drake S. Eggleston 3,6, Andrew Fosberry 3, Daniel R. Gentry 2, Fabrice Gorrec 3,6, Ilaria Giordano 4, Michael M. Hann 1, Alan Hennessy 4, Martin Hibbs 3, Jianzhong Huang 2, Emma Jones 3, Jo Jones 3, Kristin Koretke Brown 5, Ceri J. Lewis 3, Earl W. May 2,6, Martin R. Saunders 1, Onkar Singh 1, Claus E. Spitzfaden 1, Carol Shen 2, Anthony Shillings 3, Andrew J. Theobald 3, Alexandre Wohlkonig 4,6, Neil D. Pearson 2 & Michael N. Gwynn 2
1. Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
2. Antibacterial Discovery Performance Unit, Infectious Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline, 1250 Collegeville Road, Collegeville, Pennsylvania 19426, USA
3. Molecular Discovery Research, GlaxoSmithKline, Third Ave, Harlow, Essex, CM19 5AW, UK
4. Antibacterial Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
5. Molecular Discovery Research, GlaxoSmithKline, 1250 Collegeville Rd., Collegeville, Pennsylvania 19426, USA
6. Present addresses: Innovalyst, 1000 Centre Green Way, Suite 200, Cary, North Carolina 27513, USA (D.S.E.); MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 0QH, UK (F.G.); OSI Pharmaceuticals, 1 Bioscience Park Drive, Farmingdale, New York 11735, USA (E.W.M.); Vrije Universiteit Brussel, VIB Department of Molecular and Cellular Interactions, Pleinlaan 2, 1050 Brussels, Belgium (A.W.).
Correspondence to: Benjamin D. Bax1 Email: benjamin.d.bax@gsk.com
Correspondence to: Michael N. Gwynn2 Email: mick.gwynn@gsk.com
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 ? 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.
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[Source: Nature, <cite cite="http://www.nature.com/nature/journal/v466/n7309/full/nature09197.html">Access : Type IIA topoisomerase inhibition by a new class of antibacterial agents : Nature</cite>. Abstract, edited.]
Nature 466, 935-940 (19 August 2010) | doi:10.1038/nature09197; Received 11 October 2009; Accepted 20 May 2010; Published online 4 August 2010; Corrected 19 August 2010
Type IIA topoisomerase inhibition by a new class of antibacterial agents
Benjamin D. Bax 1, Pan F. Chan 2, Drake S. Eggleston 3,6, Andrew Fosberry 3, Daniel R. Gentry 2, Fabrice Gorrec 3,6, Ilaria Giordano 4, Michael M. Hann 1, Alan Hennessy 4, Martin Hibbs 3, Jianzhong Huang 2, Emma Jones 3, Jo Jones 3, Kristin Koretke Brown 5, Ceri J. Lewis 3, Earl W. May 2,6, Martin R. Saunders 1, Onkar Singh 1, Claus E. Spitzfaden 1, Carol Shen 2, Anthony Shillings 3, Andrew J. Theobald 3, Alexandre Wohlkonig 4,6, Neil D. Pearson 2 & Michael N. Gwynn 2
1. Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
2. Antibacterial Discovery Performance Unit, Infectious Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline, 1250 Collegeville Road, Collegeville, Pennsylvania 19426, USA
3. Molecular Discovery Research, GlaxoSmithKline, Third Ave, Harlow, Essex, CM19 5AW, UK
4. Antibacterial Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
5. Molecular Discovery Research, GlaxoSmithKline, 1250 Collegeville Rd., Collegeville, Pennsylvania 19426, USA
6. Present addresses: Innovalyst, 1000 Centre Green Way, Suite 200, Cary, North Carolina 27513, USA (D.S.E.); MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 0QH, UK (F.G.); OSI Pharmaceuticals, 1 Bioscience Park Drive, Farmingdale, New York 11735, USA (E.W.M.); Vrije Universiteit Brussel, VIB Department of Molecular and Cellular Interactions, Pleinlaan 2, 1050 Brussels, Belgium (A.W.).
Correspondence to: Benjamin D. Bax1 Email: benjamin.d.bax@gsk.com
Correspondence to: Michael N. Gwynn2 Email: mick.gwynn@gsk.com
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 ? 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.
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