Cumming John G, Kreis Lukas, Kühne Holger, Wermuth Roger, Vercruysse Maarten, Kramer Christian, Rudolph Markus G, Xu Zhiheng
Roche Pharma Research & Early Development, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland.
China Innovation Center of Roche, Roche R&D Center (China) Ltd., Shanghai 201203, China.
ACS Med Chem Lett. 2023 Jun 22;14(7):993-998. doi: 10.1021/acsmedchemlett.3c00187. eCollection 2023 Jul 13.
The rise of multidrug-resistant (MDR) Gram-negative bacteria is a major global health problem necessitating the discovery of new classes of antibiotics. Novel bacterial topoisomerase inhibitors (NBTIs) target the clinically validated bacterial type II topoisomerases with a distinct binding site and mechanism of action to fluoroquinolone antibiotics, thus avoiding cross-resistance to this drug class. Here we report the discovery of a series of NBTIs incorporating a novel indane DNA binding moiety. X-ray cocrystal structures of compounds and bound to DNA gyrase-DNA were determined, revealing specific interactions with the enzyme binding pocket at the GyrA dimer interface and a long-range electrostatic interaction between the basic amine in the linker and the carboxylate of Asp83. Exploration of the structure-activity relationship within the series led to the identification of lead compound , which showed potent broad-spectrum activity against a panel of MDR Gram-negative bacteria.
多重耐药（MDR）革兰氏阴性菌的出现是一个重大的全球健康问题，需要发现新型抗生素类别。新型细菌拓扑异构酶抑制剂（NBTIs）靶向经临床验证的细菌II型拓扑异构酶，其结合位点和作用机制与氟喹诺酮类抗生素不同，从而避免对该类药物产生交叉耐药性。在此，我们报告了一系列含有新型茚满DNA结合部分的NBTIs的发现。测定了化合物 和 与DNA促旋酶-DNA结合的X射线共晶体结构，揭示了在GyrA二聚体界面与酶结合口袋的特异性相互作用，以及连接子中的碱性胺与Asp83的羧酸盐之间的远程静电相互作用。对该系列化合物构效关系的探索导致了先导化合物 的鉴定，该化合物对一组MDR革兰氏阴性菌显示出强大的广谱活性。
