Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa

We have developed compounds with a promising activity
against Acinetobacter baumannii and Pseudomonas
aeruginosa, which are both on the WHO priority list
of antibiotic-resistant bacteria. Starting from DNA gyrase inhibitor 1, we identified compound 27, featuring a 10-fold
improved aqueous solubility, a 10-fold improved inhibition of topoisomerase
IV from A. baumannii and P. aeruginosa, a 10-fold decreased inhibition of
human topoisomerase IIα, and no cross-resistance to novobiocin.
Cocrystal structures of 1 in complex with Escherichia coli GyrB24 and (S)-27 in complex with A. baumannii GyrB23 and P. aeruginosa GyrB24 revealed
their binding to the ATP-binding pocket of the GyrB subunit. In further
optimization steps, solubility, plasma free fraction, and other ADME
properties of 27 were improved by fine-tuning of lipophilicity.
In particular, analogs of 27 with retained anti-Gram-negative
activity and improved plasma free fraction were identified. The series
was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial
toxicity, and possessed no ion channel liabilities.

本研究开发了对鲍曼不动杆菌（Acinetobacter baumannii）与铜绿假单胞菌（Pseudomonas aeruginosa）展现出优异抑菌活性的化合物，这两种病原菌均被列入世界卫生组织（WHO）发布的耐抗生素细菌优先名录。本研究以DNA旋转酶抑制剂（DNA gyrase inhibitor）1为先导分子，筛选得到化合物27，其水溶性提升10倍，对鲍曼不动杆菌与铜绿假单胞菌的拓扑异构酶IV（topoisomerase IV）抑制活性提升10倍，对人类拓扑异构酶IIα（human topoisomerase IIα）的抑制活性降低10倍，且对新生霉素（novobiocin）无交叉耐药性。化合物1与大肠杆菌（Escherichia coli）GyrB24形成的共晶复合物结构，以及(S)-27分别与鲍曼不动杆菌GyrB23、铜绿假单胞菌GyrB24形成的共晶复合物结构，揭示了二者均可结合于GyrB亚基的ATP结合口袋（ATP-binding pocket）。在后续优化环节中，通过微调亲脂性（lipophilicity），化合物27的水溶性、血浆游离分数及其他ADME（吸收-分布-代谢-排泄）性质均得到优化。尤为重要的是，本研究筛选获得了保留抗革兰氏阴性菌活性且血浆游离分数得到提升的27类似物。该系列化合物均被证实无遗传毒性、无致突变性，无线粒体毒性，且不存在离子通道相关不良反应。