Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Nature communications, 2015-12, Vol.6 (1), p.10048-10048, Article 10048

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2015

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.