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.

中文翻译：

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抗菌QPT-1，抗癌药依托泊苷和莫西沙星抑制DNA促旋酶的结构基础。

需要新的抗菌素来解决抗药性细菌。IIA型拓扑异构酶（topo2As）是氟喹诺酮类药物的靶标，通过产生瞬时双链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促旋酶的第一个共晶体结构，显示在裂解的DNA中与氟喹诺酮莫西沙星在相同的位点结合。与莫西沙星不同，QPT-1和依托泊苷与保守的GyrB TOPRIM残基相互作用，使QPT-1可以克服氟喹诺酮耐药性变得合理。我们的数据显示依托泊苷的抗菌活性归因于DNA促旋酶的抑制作用，并表明其他抗癌药也具有类似作用。对多个DNA促旋酶共晶体结构（包括不对称裂解复合物）的分析导致“ 一对旋转门假说，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。这种机制可以解释QPT-1的细菌特异性。建议基于结构的策略来开发topo2A抗菌剂。