Strategy for anti-tuberculosis therapy

描述（由申请人提供）：结核病是一个全球性的健康问题。传播非常有效，许多国家的社会条件使控制这种疾病变得不容易。虽然疫苗接种在世界上大多数地区都是常规的，但绝大多数人口只产生部分保护或根本没有保护。因此，结核病作为大多数传染病，用抗生素治疗。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的化合物的耐药性多年来一直在增加，并且在世界某些地区，现在是一个严重的问题。这种细菌在与杀菌化合物一起孵育后需要几天才能死亡，这是M.结核病暴露于杀菌药物。这一观察结果指导了工作方向的理解和识别病原体使用的“逃逸”途径，即使在杀菌化合物存在的情况下也能存活更长时间。我们的建议是开发新的靶点（逃逸途径靶点），与现有的靶点（和未来的新靶点）相结合，将有能力更快地杀死细菌，并防止细菌的死亡。 耐药性的出现，最终减少治疗时间。我们已经获得了这个假设的初步证据。我们建议：1.研究细菌对抗结核化合物（新的和旧的）的反应，如通过蛋白质组学反应所测量的; 2.识别和鉴定参与逃逸机制的细菌靶标。对于一对夫妇选定的化合物和目标，我们计划在巨噬细胞模型系统中初步解决该方法的可行性。该提案不仅解决了新靶点的发现，而且合理发现了目前活性化合物将以协同方式起作用的靶点，加速细菌杀灭，减少治疗时间，减少副作用的机会和特异性耐药机制的发展。

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.