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Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance

Nature Structural & Molecular Biology volume 17, pages 1152–1153 (2010)Cite this article

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Abstract

Quinolone antibacterials have been used to treat bacterial infections for over 40 years. A crystal structure of moxifloxacin in complex with Acinetobacter baumannii topoisomerase IV now shows the wedge-shaped quinolone stacking between base pairs at the DNA cleavage site and binding conserved residues in the DNA cleavage domain through chelation of a noncatalytic magnesium ion. This provides a molecular basis for the quinolone inhibition mechanism, resistance mutations and invariant quinolone antibacterial structural features.

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Figure 1: A. baumannii ParE28–ParC58 complex with moxifloxacin and DNA.
Figure 2: Mg2+ ion mediates quinolone interactions with topo IV.

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Acknowledgements

We thank D. Payne for discussions. A.W. was funded and supported by the Wellcome Trust Seeding Drug Discovery Initiative and contract HDTRA1-07-9-0002 with the US Department of Defense Joint Science and Technology Office for Chemical and Biological Defense and the Defense Threat Reduction Agency's Transformational Medical Technologies. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the US Department of Defense or the US Government.

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Authors and Affiliations

  1. Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire, UK

    Alexandre Wohlkonig, Andrew P Fosberry, Paul Homes, Michael Kranz, Vaughan R Leydon, Rajika L Perera, Anthony J Shillings & Benjamin D Bax

  2. Antibacterial Discovery Performance Unit, Infectious Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline, Collegeville, Pennsylvania, USA

    Pan F Chan, Jianzhong Huang, Neil D Pearson & Michael N Gwynn

  3. Antibacterial Discovery Performance Unit, Infectious Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire, UK

    Timothy J Miles

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  1. Alexandre Wohlkonig
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Contributions

B.D.B. and M.N.G. designed experiments; A.P.F., P.H., V.R.L., R.L.P. and A.J.S. cloned, expressed and isolated ParE28–ParC58; P.F.C. and J.H. performed enzyme assays; A.W. crystallized the complex, and A.W. and B.D.B. determined its structure; T.J.M. and N.D.P. interpreted SAR; M.K. ran ab initio calculations and analyzed structures from the CSD; A.W., B.D.B. and M.N.G. wrote the manuscript.

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Correspondence to Michael N Gwynn or Benjamin D Bax.

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The authors declare no competing financial interests.

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Supplementary Table 1, Supplementary Figures 1–11 and Supplementary Methods (PDF 2561 kb)

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Wohlkonig, A., Chan, P., Fosberry, A. et al. Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance. Nat Struct Mol Biol 17, 1152–1153 (2010). https://doi.org/10.1038/nsmb.1892

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