Discovery of Benzothiazole Scaffold-Based DNA Gyrase B Inhibitors

Bacterial
DNA gyrase and topoisomerase IV control the topological
state of DNA during replication and are validated targets for antibacterial
drug discovery. Starting from our recently reported 4,5,6,7-tetrahydro­benzo­[1,2-d]­thiazole-based DNA gyrase B inhibitors, we replaced their
central core with benzothiazole-2,6-diamine scaffold and interchanged
substituents in positions 2 and 6. This resulted in equipotent nanomolar
inhibitors of DNA gyrase from Escherichia coli displaying
improved inhibition of Staphylococcus aureus DNA
gyrase and topoisomerase IV from both bacteria. Compound 27 was the most balanced inhibitor of DNA gyrase and topoisomerase
IV from both E. coli and S. aureus. The crystal structure of the 2-((2-(4,5-dibromo-1H-pyrrole-2-carboxamido)­benzothiazol-6-yl)­amino)-2-oxoacetic
acid (24) in complex with E. coli DNA
gyrase B revealed the binding mode of the inhibitor in the ATP-binding
pocket. Only some compounds possessed weak antibacterial activity
against Gram-positive bacteria. These results provide a basis for
structure-based optimization toward dual DNA gyrase and topoisomerase
IV inhibitors with antibacterial activity.

细菌DNA旋转酶（DNA gyrase）与拓扑异构酶IV（topoisomerase IV）可在DNA复制过程中调控DNA的拓扑状态，是抗菌药物研发的已验证靶点。
基于本团队近期报道的4,5,6,7-四氢苯并[1,2-d]噻唑类DNA旋转酶B亚基抑制剂，我们将其核心骨架替换为苯并噻唑-2,6-二胺骨架，并对2位与6位的取代基进行了互换。
该改造得到了对大肠杆菌（Escherichia coli）DNA旋转酶抑制活性等效的纳摩尔级抑制剂，且对金黄色葡萄球菌（Staphylococcus aureus）DNA旋转酶以及两种受试细菌的拓扑异构酶IV均展现出更优的抑制活性。
化合物27是同时针对大肠杆菌与金黄色葡萄球菌的DNA旋转酶及拓扑异构酶IV，抑制活性最为均衡的抑制剂。
2-((2-(4,5-二溴-1H-吡咯-2-甲酰胺基)苯并噻唑-6-基)氨基)-2-氧代乙酸（24）与大肠杆菌DNA旋转酶B亚基复合物的晶体结构，揭示了该抑制剂在ATP结合口袋（ATP-binding pocket）中的结合模式。
仅部分化合物对革兰氏阳性菌（Gram-positive bacteria）展现出较弱的抗菌活性。
本研究结果为开发兼具抗菌活性的双重DNA旋转酶与拓扑异构酶IV抑制剂的基于结构的优化工作提供了理论依据。