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

被引：123

作者：

Chan, Pan F. ^{[1
]}

Srikannathasan, Velupillai ^{[2
]}

Huang, Jianzhong ^{[1
]}

Cui, Haifeng ^{[1
]}

Fosberry, Andrew P. ^{[2
]}

Gu, Minghua ^{[1
]}

Hann, Michael M. ^{[2
]}

Hibbs, Martin ^{[2
]}

Homes, Paul ^{[2
]}

Ingraham, Karen ^{[1
]}

Pizzollo, Jason ^{[1
]}

Shen, Carol ^{[1
]}

Shillings, Anthony J. ^{[2
]}

Spitzfaden, Claus E. ^{[2
]}

Tanner, Robert ^{[2
]}

Theobald, Andrew J. ^{[2
]}

Stavenger, Robert A. ^{[1
]}

Bax, Benjamin D. ^{[2
]}

Gwynn, Michael N. ^{[1
]}

机构：

[1] GlaxoSmithKline, Antibacterial Discovery Performance Unit, Infect Dis, Therapy Area Unit, Collegeville, PA 19426 USA

[2] GlaxoSmithKline, Platform Technol & Sci, Med Res Ctr, Stevenage SG1 2NY, Herts, England

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

基金：

英国惠康基金;

关键词：

IN-VITRO ACTIVITY; TOPOISOMERASE-IV; QUINOLONE RESISTANCE; II TOPOISOMERASES; MECHANISM; AZD0914; REFINEMENT; COMPLEXES; MUTATION; SENSITIVITY;

D O I：

10.1038/ncomms10048

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：13

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