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

Alexandre Wohlkonig; Pan F Chan; Andrew P Fosberry; Paul Homes; Jianzhong Huang; Michael Kranz; Vaughan R Leydon; Timothy J Miles; Neil D Pearson; Rajika L Perera; Anthony J Shillings; Michael N Gwynn; Benjamin D Bax

doi:10.1038/nsmb.1892

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

Alexandre Wohlkonig, Pan F Chan, Andrew P Fosberry, Paul Homes, Jianzhong Huang, Michael Kranz, Vaughan R Leydon, Timothy J Miles, Neil D Pearson, Rajika L Perera, Anthony J Shillings, Michael N Gwynn, Benjamin D Bax

Research output: Contribution to journal › Article › peer-review

257 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1152-1153
Number of pages	2
Journal	Nature Structural & Molecular Biology
Volume	17
Issue number	9
DOIs	https://doi.org/10.1038/nsmb.1892
Publication status	Published - Sep 2010

Keywords

Acinetobacter baumannii/enzymology
DNA Topoisomerase IV/chemistry
Enzyme Inhibitors/chemistry
Models, Molecular
Protein Structure, Quaternary
Protein Structure, Tertiary
Quinolones/chemistry

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Wohlkonig, A., Chan, P. F., Fosberry, A. P., Homes, P., Huang, J., Kranz, M., Leydon, V. R., Miles, T. J., Pearson, N. D., Perera, R. L., Shillings, A. J., Gwynn, M. N., & Bax, B. D. (2010). Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance. Nature Structural & Molecular Biology, 17(9), 1152-1153. https://doi.org/10.1038/nsmb.1892

Wohlkonig, Alexandre ; Chan, Pan F ; Fosberry, Andrew P ; Homes, Paul ; Huang, Jianzhong ; Kranz, Michael ; Leydon, Vaughan R ; Miles, Timothy J ; Pearson, Neil D ; Perera, Rajika L ; Shillings, Anthony J ; Gwynn, Michael N ; Bax, Benjamin D. / Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance. In: Nature Structural & Molecular Biology. 2010 ; Vol. 17, No. 9. pp. 1152-1153.

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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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Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance. / Wohlkonig, Alexandre; Chan, Pan F; Fosberry, Andrew P; Homes, Paul; Huang, Jianzhong; Kranz, Michael; Leydon, Vaughan R; Miles, Timothy J; Pearson, Neil D; Perera, Rajika L; Shillings, Anthony J; Gwynn, Michael N; Bax, Benjamin D.

In: Nature Structural & Molecular Biology, Vol. 17, No. 9, 09.2010, p. 1152-1153.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance

AU - Wohlkonig, Alexandre

AU - Chan, Pan F

AU - Fosberry, Andrew P

AU - Homes, Paul

AU - Huang, Jianzhong

AU - Kranz, Michael

AU - Leydon, Vaughan R

AU - Miles, Timothy J

AU - Pearson, Neil D

AU - Perera, Rajika L

AU - Shillings, Anthony J

AU - Gwynn, Michael N

AU - Bax, Benjamin D

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AB - 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.

KW - Acinetobacter baumannii/enzymology

KW - DNA Topoisomerase IV/chemistry

KW - Enzyme Inhibitors/chemistry

KW - Models, Molecular

KW - Protein Structure, Quaternary

KW - Protein Structure, Tertiary

KW - Quinolones/chemistry

U2 - 10.1038/nsmb.1892

DO - 10.1038/nsmb.1892

M3 - Article

C2 - 20802486

VL - 17

SP - 1152

EP - 1153

JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

SN - 1545-9993

IS - 9

ER -

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

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Keywords

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