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

Pan F. Chan (), Velupillai Srikannathasan, Jianzhong Huang, Haifeng Cui, Andrew P. Fosberry, Minghua Gu, Michael M. Hann, Martin Hibbs, Paul Homes, Karen Ingraham, Jason Pizzollo, Carol Shen, Anthony J. Shillings, Claus E. Spitzfaden, Robert Tanner, Andrew J. Theobald, Robert A. Stavenger, Benjamin D. Bax () and Michael N. Gwynn
Additional contact information
Pan F. Chan: Antibacterial Discovery Performance Unit, Infectious Diseases, Therapy Area Unit, GlaxoSmithKline
Velupillai Srikannathasan: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre
Jianzhong Huang: Antibacterial Discovery Performance Unit, Infectious Diseases, Therapy Area Unit, GlaxoSmithKline
Haifeng Cui: Antibacterial Discovery Performance Unit, Infectious Diseases, Therapy Area Unit, GlaxoSmithKline
Andrew P. Fosberry: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre
Minghua Gu: Antibacterial Discovery Performance Unit, Infectious Diseases, Therapy Area Unit, GlaxoSmithKline
Michael M. Hann: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre
Martin Hibbs: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre
Paul Homes: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre
Karen Ingraham: Antibacterial Discovery Performance Unit, Infectious Diseases, Therapy Area Unit, GlaxoSmithKline
Jason Pizzollo: Antibacterial Discovery Performance Unit, Infectious Diseases, Therapy Area Unit, GlaxoSmithKline
Carol Shen: Antibacterial Discovery Performance Unit, Infectious Diseases, Therapy Area Unit, GlaxoSmithKline
Anthony J. Shillings: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre
Claus E. Spitzfaden: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre
Robert Tanner: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre
Andrew J. Theobald: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre
Robert A. Stavenger: Antibacterial Discovery Performance Unit, Infectious Diseases, Therapy Area Unit, GlaxoSmithKline
Benjamin D. Bax: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre
Michael N. Gwynn: Antibacterial Discovery Performance Unit, Infectious Diseases, Therapy Area Unit, GlaxoSmithKline

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms10048

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