Strategy for anti-tuberculosis therapy

描述(申请人提供)：结核病是一个世界性的健康问题。传播是非常有效的，许多国家的社会条件并不容易控制这种疾病。虽然疫苗接种在世界大多数地区是例行公事，但绝大多数人口只获得部分保护或根本没有保护。因此，结核病作为大多数传染病，都是用抗生素治疗的。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抗药性多年来一直在增加，在世界某些地区现在是一个严重的问题。在与一种杀菌化合物孵育后，这种细菌需要几天时间才能死亡，这是接触杀菌药物的结核分枝杆菌的常态。这一观察指导了工作的方向，即理解和识别病原体使用的“逃逸”途径，以延长生存时间，即使在存在杀菌化合物的情况下也是如此。我们的建议是开发新的靶标(逃逸途径靶标)，与现有的靶标(和未来的新靶标)相结合，将有能力更快地杀死细菌，并防止 耐药性的出现，最终缩短了治疗时间。我们已经获得了支持这一假设的初步证据。我们建议：1.通过蛋白质组学反应来研究细菌对抗结核化合物(新的和旧的)的反应；2.识别和灭活参与逃逸机制的细菌靶点。对于一些选定的化合物和靶点，我们计划在巨噬细胞模型系统中初步探讨该方法的可行性。该提案不仅涉及发现新的靶点，还涉及合理发现目前有效的化合物将以协同方式发挥作用的靶点，加速杀菌，缩短治疗时间，减少副作用的机会，并发展特定的耐药机制。

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.