Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin.
Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin.
复制标题
抗菌QPT-1，抗癌药物依托泊苷和莫西沙星抑制DNA循环酶的结构基础。
DOI：
10.1038/ncomms10048
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发表时间：
2015-12-07
影响因子：
16.6
通讯作者：
Gwynn MN
中科院分区：
文献类型：
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作者：
Chan PF;Srikannathasan V;Huang J;Cui H;Fosberry AP;Gu M;Hann MM;Hibbs M;Homes P;Ingraham K;Pizzollo J;Shen C;Shillings AJ;Spitzfaden CE;Tanner R;Theobald AJ;Stavenger RA;Bax BD;Gwynn MN
需要新的抗菌药物来对付耐药性细菌。IIA型拓扑异构酶（topo 2As）是氟喹诺酮类药物的靶点，通过产生短暂的双链DNA断裂来调节DNA拓扑结构。在这里，我们报告的抗菌QPT-1和抗癌药物依托泊苷与金黄色葡萄球菌DNA旋转酶的第一个共晶体结构，显示在相同的网站在切割的DNA作为氟喹诺酮类药物氟诺沙星的结合。与氟喹诺酮类药物不同，QPT-1和依托泊苷与保守的GyrB TOPRIM残基相互作用，从而合理解释了QPT-1为何能够克服氟喹诺酮类药物耐药性。我们的数据显示依托泊苷的抗菌活性是由于DNA促旋酶抑制，并表明其他抗癌药物的作用类似。对多个DNA促旋酶共晶体结构（包括不对称切割复合物）的分析导致了一种“对摆动门”假说，其中一个DNA片段的运动调节第二个DNA双链体的切割和重新连接。这一机制可以解释QPT-1的细菌特异性。提出了基于结构的topo 2A抗菌药物开发策略。 IIA型拓扑异构酶（topo 2As）产生瞬时双链DNA断裂。在这里，作者报告了QPT-1如何在DNA/topo 2A复合物中与氟喹诺酮类药物氟喹诺酮沙星结合的结构，并讨论了开发新型抗生素的潜力。
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. Type IIA topoisomerases (topo2As) create transient double-strand DNA breaks. Here, the authors report structures showing how QPT-1 binds in the DNA/topo2A complex at the same site as the fluoroquinolone moxifloxacin, and discuss the potential for developing new classes of antibiotics.