Phua Zheng Yen, Li Ming, Ali Azhar, Cheong Cedric Cheng Sheng, Goh Kai Jie, Seto Marcus Yi Kang, Ng Amos Shi Ying, Sarathy Jickky Palmae, Goh Boon Cher, Go Mei Lin, Chui Wai Keung, Dick Thomas, Lam Yulin
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore.
Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Dr, Singapore 117599, Singapore.
iScience. 2025 Jun 18;28(7):112915. doi: 10.1016/j.isci.2025.112915. eCollection 2025 Jul 18.
Clinically efficacious combination therapies capable of impeding resistance are widely sought for the treatment of mycobacterial infections. Here, we described structural modifications of the phenylalkylamine scaffold of verapamil to give an analog with more than 10-fold greater growth inhibitory activity than verapamil against , BCG, and The analog synergized with the FF-ATP synthase inhibitor bedaquiline in checkerboard assays and augmented the bactericidal properties of bedaquiline against BCG and . Using live cell bioorthogonal imaging techniques, biochemical and genetic assays, the bactericidal activity of the analog is attributed to the perturbation of membrane bioenergetics and disruption of mycobacterial respiration. Overall, its promising activity profile, mode of action and synergistic interaction with bedaquiline support further exploration of the phenylalkylamine scaffold as a valued source of potential leads for antimycobacterial drug discovery.
临床上迫切需要能够阻止耐药性的有效联合疗法来治疗分枝杆菌感染。在此，我们描述了维拉帕米苯烷基胺支架的结构修饰，得到了一种类似物，其对卡介苗和结核分枝杆菌的生长抑制活性比维拉帕米高10倍以上。在棋盘试验中，该类似物与FF-ATP合酶抑制剂贝达喹啉协同作用，并增强了贝达喹啉对卡介苗和结核分枝杆菌的杀菌特性。使用活细胞生物正交成像技术、生化和遗传分析，该类似物的杀菌活性归因于膜生物能学的扰动和分枝杆菌呼吸的破坏。总体而言，其有前景的活性谱、作用方式以及与贝达喹啉的协同相互作用支持进一步探索苯烷基胺支架作为抗分枝杆菌药物发现潜在先导物的重要来源。
