Kingdon Alexander D H, Adcock Holly V, Kasimati Eleni-Marina, Craven Philip, van Schaik Willem, Cox Liam R, Besra Gurdyal S
School of Biosciences, University of Birmingham, Birmingham, B15 2TT, UK.
Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, L3 5QA, UK.
J Antibiot (Tokyo). 2025 Jan;78(1):54-63. doi: 10.1038/s41429-024-00781-9. Epub 2024 Oct 15.
Mycobacterium tuberculosis is a bacterial pathogen, responsible for approximately 1.3 million deaths in 2022 through tuberculosis infections. The complex treatment regimen required to treat tuberculosis and growing rates of drug resistance, necessitates the development of new anti-mycobacterial agents. One approach is to repurpose drugs from other clinical applications. Vanoxerine (GBR 12909) was previously shown to have anti-mycobacterial activity, through dissipating the membrane electric potential and hence, cellular energetics. Several vanoxerine analogues were synthesised in this study, which exhibited a range of activities against mycobacteria and enterococcus. All active analogues had similar impacts on the membrane electric potential and inhibition of ethidium bromide efflux. The most active compound displayed reduced inhibitory activity against the known human target of vanoxerine, the dopamine transporter. This work has identified a promising analogue, which could provide a starting point for further medicinal chemistry and drug development efforts to target mycobacteria.
结核分枝杆菌是一种细菌病原体，2022年因结核病感染导致约130万人死亡。治疗结核病所需的复杂治疗方案以及不断上升的耐药率，使得开发新型抗分枝杆菌药物成为必要。一种方法是将其他临床应用中的药物重新用于此用途。先前的研究表明，瓦诺西汀（GBR 12909）通过消散膜电位进而影响细胞能量代谢，具有抗分枝杆菌活性。本研究合成了几种瓦诺西汀类似物，它们对分枝杆菌和肠球菌表现出一系列活性。所有活性类似物对膜电位和溴化乙锭外排的抑制作用相似。活性最强的化合物对瓦诺西汀已知的人类靶点多巴胺转运体的抑制活性降低。这项工作鉴定出了一种有前景的类似物，可为进一步针对分枝杆菌的药物化学和药物开发工作提供一个起点。
