Xiang Wang, He Hualong, Duan Xianjie, He Zhiqun, Xu Xinyue, Liao Mengya, Teng Fei, Li Xiao, Luo Tianwen, Zeng Jumei, Yu Luoting, Gao Chao
State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University , Chengdu, Sichuan, China.
West China School of Public Health and West China Fourth Hospital, Sichuan University , Chengdu, Sichuan, China.
Microbiol Spectr. 2023 Sep 12;11(5):e0472122. doi: 10.1128/spectrum.04721-22.
About a quarter of the world's population is infected with , equivalent to about two billion people. With the emergence of multidrug-resistant tuberculosis, those existing anti-tuberculosis drugs no longer meet the demand for cure anymore; there is an urgent need for the development of new anti-tuberculosis drugs. Decaprenylphosphoryl-β-D-ribose 2´-epimerase (DprE1) has been proven to be a potential antimycobacterial target, and several inhibitors have entered clinical trial. Herein, we designed and synthesized a series of compounds based on the indole and benzomorpholine by using the strategy of scaffold hopping. The preferred compound showed strong antimycobacterial activity in H37Rv and drug-resistant clinical isolates. In addition, compound did not exhibit antimycobacterial efficacy against other species of strains. Subsequently, the target of was identified as DprE1 by analyzing spontaneous compound-resistant mutation data, and a docking study was performed to illustrate the binding mode between and DprE1. In general, compound is compatible to current DprE1 inhibitors, even higher phosphodiesterase 6C selectivity and plasma protein binding rate, which represent a new type of effective reversible DprE1 inhibitor. IMPORTANCE Drug therapy remains the cornerstone of tuberculosis (TB) treatment, yet first-line anti-tuberculosis drugs are associated with significant adverse effects that can compromise patient outcomes. Moreover, prolonged and widespread use has led to an alarming rise in drug-resistant strains of , including multidrug-resistant [MDR-tuberculosis (TB)] and extensively drug-resistant (XDR-TB) forms. Urgent action is needed to develop novel anti-tuberculosis agents capable of overcoming these challenges. We report that compound , a decaprenylphosphoryl-β-D-ribose 2´-epimerase inhibitor with a benzomorpholine backbone, exhibits potent activity against not only the non-pathogenic strain H37Ra, but also the pathogenic strain H37Rv and clinical MDR and XDR strains. Preliminary druggability studies indicate that possesses high safety and acceptable pharmacokinetic properties, rendering it a promising candidate for further development as a novel anti-tuberculosis agent.
全球约四分之一的人口感染了（结核菌），约二十亿人。随着多重耐药结核病的出现，现有的抗结核药物已无法满足治愈需求；迫切需要研发新型抗结核药物。癸异戊二烯基磷酸化-β-D-核糖2´-表异构酶（DprE1）已被证明是一个潜在的抗分枝杆菌靶点，并且几种抑制剂已进入临床试验阶段。在此，我们采用骨架跃迁策略，基于吲哚和苯并吗啉设计并合成了一系列化合物。优选化合物在H37Rv和耐药临床分离株中表现出较强的抗分枝杆菌活性。此外，该化合物对其他菌株无抗分枝杆菌功效。随后，通过分析自发的化合物耐药突变数据确定该化合物的作用靶点为DprE1，并进行了对接研究以阐明该化合物与DprE1之间的结合模式。总体而言，该化合物与目前的DprE1抑制剂具有相容性，甚至具有更高的磷酸二酯酶6C选择性和血浆蛋白结合率，代表了一种新型的有效可逆DprE1抑制剂。重要性药物治疗仍然是结核病治疗的基石，但一线抗结核药物具有显著的副作用，可能会影响患者的治疗效果。此外，长期广泛使用已导致结核菌耐药菌株惊人地增加，包括多重耐药[耐多药结核病（MDR-TB）]和广泛耐药（XDR-TB）形式。迫切需要采取行动研发能够克服这些挑战的新型抗结核药物。我们报告称，化合物（一种具有苯并吗啉骨架的癸异戊二烯基磷酸化-β-D-核糖2´-表异构酶抑制剂）不仅对非致病菌株H37Ra具有强效活性，而且对致病菌株H37Rv以及临床MDR和XDR菌株也具有强效活性。初步的成药可行性研究表明，该化合物具有高安全性和可接受的药代动力学特性，使其成为作为新型抗结核药物进一步开发的有前景的候选药物。
