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Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin

New antibacterials are needed to tackle antibiotic-resistant bacteria. Type IIA topoisomerases (topo2As), the targets of fluoroquinolones, regulate DNA topology by creating transient double-strand DNA breaks. Here we report the first co-crystal structures of the antibacterial QPT-1 and the anticance...

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Autores principales: Chan, Pan F., Srikannathasan, Velupillai, Huang, Jianzhong, Cui, Haifeng, Fosberry, Andrew P., Gu, Minghua, Hann, Michael M., Hibbs, Martin, Homes, Paul, Ingraham, Karen, Pizzollo, Jason, Shen, Carol, Shillings, Anthony J., Spitzfaden, Claus E., Tanner, Robert, Theobald, Andrew J., Stavenger, Robert A., Bax, Benjamin D., Gwynn, Michael N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4686662/
https://www.ncbi.nlm.nih.gov/pubmed/26640131
http://dx.doi.org/10.1038/ncomms10048
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author Chan, Pan F.
Srikannathasan, Velupillai
Huang, Jianzhong
Cui, Haifeng
Fosberry, Andrew P.
Gu, Minghua
Hann, Michael M.
Hibbs, Martin
Homes, Paul
Ingraham, Karen
Pizzollo, Jason
Shen, Carol
Shillings, Anthony J.
Spitzfaden, Claus E.
Tanner, Robert
Theobald, Andrew J.
Stavenger, Robert A.
Bax, Benjamin D.
Gwynn, Michael N.
author_facet Chan, Pan F.
Srikannathasan, Velupillai
Huang, Jianzhong
Cui, Haifeng
Fosberry, Andrew P.
Gu, Minghua
Hann, Michael M.
Hibbs, Martin
Homes, Paul
Ingraham, Karen
Pizzollo, Jason
Shen, Carol
Shillings, Anthony J.
Spitzfaden, Claus E.
Tanner, Robert
Theobald, Andrew J.
Stavenger, Robert A.
Bax, Benjamin D.
Gwynn, Michael N.
author_sort Chan, Pan F.
collection PubMed
description New antibacterials are needed to tackle antibiotic-resistant bacteria. Type IIA topoisomerases (topo2As), the targets of fluoroquinolones, regulate DNA topology by creating transient double-strand DNA breaks. Here we report the first co-crystal structures of the antibacterial QPT-1 and the anticancer drug etoposide with Staphylococcus aureus DNA gyrase, showing binding at the same sites in the cleaved DNA as the fluoroquinolone moxifloxacin. Unlike moxifloxacin, QPT-1 and etoposide interact with conserved GyrB TOPRIM residues rationalizing why QPT-1 can overcome fluoroquinolone resistance. Our data show etoposide's antibacterial activity is due to DNA gyrase inhibition and suggests other anticancer agents act similarly. Analysis of multiple DNA gyrase co-crystal structures, including asymmetric cleavage complexes, led to a ‘pair of swing-doors' hypothesis in which the movement of one DNA segment regulates cleavage and religation of the second DNA duplex. This mechanism can explain QPT-1's bacterial specificity. Structure-based strategies for developing topo2A antibacterials are suggested.
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spelling pubmed-46866622016-01-07 Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin Chan, Pan F. Srikannathasan, Velupillai Huang, Jianzhong Cui, Haifeng Fosberry, Andrew P. Gu, Minghua Hann, Michael M. Hibbs, Martin Homes, Paul Ingraham, Karen Pizzollo, Jason Shen, Carol Shillings, Anthony J. Spitzfaden, Claus E. Tanner, Robert Theobald, Andrew J. Stavenger, Robert A. Bax, Benjamin D. Gwynn, Michael N. Nat Commun Article New antibacterials are needed to tackle antibiotic-resistant bacteria. Type IIA topoisomerases (topo2As), the targets of fluoroquinolones, regulate DNA topology by creating transient double-strand DNA breaks. Here we report the first co-crystal structures of the antibacterial QPT-1 and the anticancer drug etoposide with Staphylococcus aureus DNA gyrase, showing binding at the same sites in the cleaved DNA as the fluoroquinolone moxifloxacin. Unlike moxifloxacin, QPT-1 and etoposide interact with conserved GyrB TOPRIM residues rationalizing why QPT-1 can overcome fluoroquinolone resistance. Our data show etoposide's antibacterial activity is due to DNA gyrase inhibition and suggests other anticancer agents act similarly. Analysis of multiple DNA gyrase co-crystal structures, including asymmetric cleavage complexes, led to a ‘pair of swing-doors' hypothesis in which the movement of one DNA segment regulates cleavage and religation of the second DNA duplex. This mechanism can explain QPT-1's bacterial specificity. Structure-based strategies for developing topo2A antibacterials are suggested. Nature Publishing Group 2015-12-07 /pmc/articles/PMC4686662/ /pubmed/26640131 http://dx.doi.org/10.1038/ncomms10048 Text en Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Chan, Pan F.
Srikannathasan, Velupillai
Huang, Jianzhong
Cui, Haifeng
Fosberry, Andrew P.
Gu, Minghua
Hann, Michael M.
Hibbs, Martin
Homes, Paul
Ingraham, Karen
Pizzollo, Jason
Shen, Carol
Shillings, Anthony J.
Spitzfaden, Claus E.
Tanner, Robert
Theobald, Andrew J.
Stavenger, Robert A.
Bax, Benjamin D.
Gwynn, Michael N.
Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin
title Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin
title_full Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin
title_fullStr Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin
title_full_unstemmed Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin
title_short Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin
title_sort structural basis of dna gyrase inhibition by antibacterial qpt-1, anticancer drug etoposide and moxifloxacin
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4686662/
https://www.ncbi.nlm.nih.gov/pubmed/26640131
http://dx.doi.org/10.1038/ncomms10048
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