Strategy for anti-tuberculosis therapy

描述（申请人提供）：结核病是一个全球性的健康问题。传播非常有效，而且许多国家的社会条件使控制这种疾病不容易。虽然疫苗接种在世界大多数地区是常规的，但绝大多数人口只得到部分保护或根本没有保护。因此，作为大多数传染病，结核病是用抗生素治疗的。目前使用的方案是在40-50多年前引入的，结核分枝杆菌对治疗中化合物的耐药性多年来一直在增加，在世界某些地区，现在已成为一个严重问题。这种细菌在与杀菌化合物孵育后需要数天才能死亡，这是暴露于杀菌药物的结核分枝杆菌的正常情况。这一观察结果指导了工作的方向，即理解和确定病原体用来延长生存时间的“逃逸”途径，即使在杀菌化合物存在的情况下也是如此。我们的建议是开发新的靶标（逃逸途径靶标），结合现有的靶标（以及未来的新靶标），将有能力更快地杀死细菌，并预防

DESCRIPTION (provided by applicant): Tuberculosis is a worldwide health problem. Transmission is very efficient, and social conditions in many countries do not make it easy to control the disease. While vaccination is routine in most of the world, the great majority of the population only develops partial protection or no protection at all. Thus, tuberculosis, as the majority of infectious diseases, is treated with antibiotics. The regimen currently in use was introduced more than 40-50 years ago, and Mycobacterium tuberculosis resistance to the compounds in the treatment has been increasing for many years and, in certain regions of the world, is now a severe problem. The bacterium takes several days to die following incubation with a bactericidal compound, which is a norm for M. tuberculosis exposed to bactericidal drugs. The observation has guided the work in the direction of understanding and identifying "escape" pathways used by the pathogen to survive longer, even in presence of a bactericidal compound. Our proposal is to develop new targets (escape pathways targets) that, combined with existing targets (and future novel targets), will have the ability to kill the bacterium faster, and prevent the emergence of resistance, ultimately decreasing the time of therapy. We already have obtained preliminary evidence for this hypothesis. We propose: 1. to study the bacterial response to anti-tuberculosis compounds (new and old ones) as measured by the proteomic response; 2. To identify and inactivate bacterial targets involved in the escape mechanism. For a couple selected compounds and targets, we plan to address preliminarily the viability of the approach in the macrophage model system. The proposal not only addresses the discovery of novel targets, but the rational discovery of targets for which currently active compounds will act in the synergistic manner, accelerating bacterial killing, decreasing the time of therapy, decreasing the chances for side effects and the development of specific resistance mechanisms.