Unit of anti-tuberculosis immunity, CAS Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
Department of Medical Microbiology and Parasitology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Sci Rep. 2016 Sep 7;6:32725. doi: 10.1038/srep32725.
While there is an urgent need to develop new and effective drugs for treatment of tuberculosis (TB) and multi-drug resistant TB (MDR-TB), repurposing FDA (U.S. Food and Drug Administration) -approved drugs for development of anti-TB agents may decrease time and effort from bench to bedside. Here, we employed host cell-based high throughput screening (HTS) assay to screen and characterize FDA-approved, off-patent library drugs for anti-Mycobacterium tuberculosis (MTB) activities. The cell-based HTS allowed us to identify an anti-cancer drug of bis-biguanide dihydrochloride (BBD) as potent anti-mycobacteria agent. Further characterization showed that BBD could inhibit intracellular and extracellular growth of M. smegmatis and slow-growing M. bovis BCG. BBD also potently inhibited replication of clinically-isolated MTB and MDR-TB strains. The proof-of-concept study showed that BBD treatment of MTB-infected mice could significantly decrease CFU counts in the lung and spleen. Notably, comparative evaluation showed that MTB CFU counts in BBD-treated mice were lower than those in rifampicin-treated mice. No apparent BBD side effects were found in BBD-treated mice. Thus, our findings support further studies to develop BBD as a new and effective drug against TB and MDR-TB.
虽然迫切需要开发新的、有效的抗结核病（TB）和耐多药结核病（MDR-TB）药物，但将已获得美国食品和药物管理局（FDA）批准的药物重新用于开发抗结核药物，可能会减少从实验室到病床的时间和精力。在这里，我们采用基于宿主细胞的高通量筛选（HTS）方法筛选和鉴定已获得 FDA 批准、已过期的专利药物库，以寻找抗结核药物。基于细胞的 HTS 使我们能够识别出一种双胍二盐酸盐（BBD）抗癌药物，该药物具有很强的抗分枝杆菌活性。进一步的特征鉴定表明，BBD 能够抑制分枝杆菌的胞内和胞外生长，包括生长缓慢的牛分枝杆菌卡介苗。BBD 还能有效抑制临床分离的结核分枝杆菌和耐多药结核分枝杆菌的复制。概念验证研究表明，BBD 治疗感染 MTB 的小鼠可以显著降低肺和脾中的 CFU 计数。值得注意的是，比较评估表明，BBD 治疗组小鼠中的 MTB CFU 计数低于利福平治疗组。在 BBD 治疗组的小鼠中未发现明显的 BBD 副作用。因此，我们的研究结果支持进一步研究，以开发 BBD 作为一种新的、有效的抗结核病和耐多药结核病药物。
