Tomioka Haruaki
Department of Microbiology and Immunology, Shimane University School of Medicine, 89-1, Enyacho, Izumo-shi, Shimane 693-8501, Japan.
Kekkaku. 2010 Nov;85(11):815-22.
Worldwide, tuberculosis remains the most frequent and important infectious disease to cause morbidity and death. However, the development of new drugs for the treatment and prophylaxis of TB has been slow. Therefore, novel types of antituberculous drugs, which act on the unique drug targets in Mycobacterium tuberculosis, particularly the drug targets related to the establishment of mycobacterial dormancy in host's macrophages, are urgently needed. In this context, it should be noted that current antituberculous drugs mostly target the metabolic reactions and proteins which are essential for the growth of M. tuberculosis in extracellular milieus. It may also be promising to develop another type of drug that exerts an inhibitory action against bacterial virulence factors which cross talk and interfere with signaling pathways of M. tuberculosis-infected host immunocompetent cells such as lymphocytes, macrophages and NK cells, thereby changing the intracellular milieus favorable to intramacrophage survival and growth of infected bacilli. In this review article, I will describe recent approaches to identify and establish novel potential drug targets in M. tuberculosis, especially those related to mycobacterial virulence, dormancy, and cross-talk with cellular signaling pathways.
在全球范围内,结核病仍然是导致发病和死亡的最常见且最重要的传染病。然而,用于治疗和预防结核病的新药研发进展缓慢。因此,迫切需要新型抗结核药物,这些药物作用于结核分枝杆菌独特的药物靶点,特别是与结核分枝杆菌在宿主巨噬细胞中建立休眠相关的药物靶点。在此背景下,应当注意的是,目前的抗结核药物大多靶向结核分枝杆菌在细胞外环境中生长所必需的代谢反应和蛋白质。研发另一种对细菌毒力因子具有抑制作用的药物也可能具有前景,这些毒力因子相互作用并干扰结核分枝杆菌感染的宿主免疫活性细胞(如淋巴细胞、巨噬细胞和自然杀伤细胞)的信号通路,从而改变有利于感染杆菌在巨噬细胞内存活和生长的细胞内环境。在这篇综述文章中,我将描述近期在结核分枝杆菌中识别和确立新型潜在药物靶点的方法,尤其是那些与分枝杆菌毒力、休眠以及与细胞信号通路相互作用相关的靶点。