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Type IIA topoisomerase inhibition by a new class of antibacterial agents

Author

Listed:
  • 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
    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.).)

  • 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
    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.).)

  • 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
    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.).)

  • 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
    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.).)

  • 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)

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.

Suggested Citation

  • 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 Jon, 2010. "Type IIA topoisomerase inhibition by a new class of antibacterial agents," Nature, Nature, vol. 466(7309), pages 935-940, August.
    • Handle: RePEc:nat:nature:v:466:y:2010:i:7309:d:10.1038_nature09197
    DOI: 10.1038/nature09197
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    Cited by:

    1. Xi Yang & Sourav Saha & Wei Yang & Keir C. Neuman & Yves Pommier, 2022. "Structural and biochemical basis for DNA and RNA catalysis by human Topoisomerase 3β," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Shahul Hameed P & Harish Kotakonda & Sreevalli Sharma & Radha Nandishaiah & Nainesh Katagihallimath & Ranga Rao & Claire Sadler & Ian Slater & Michael Morton & Abhijeeth Chandrasekaran & Ed Griffen & , 2024. "BWC0977, a broad-spectrum antibacterial clinical candidate to treat multidrug resistant infections," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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