A "radical" approach to tuberculosis infection

绝对。结核病仍然是一种发病率和死亡率都很高的疾病。使ITS复杂化 管理是其多样化的表现，从急性疾病到潜伏感染。据估计， 世界上三分之一的人口患有潜伏性结核病，这导致了一个巨大的蓄水池，从重新激活到急性 疾病可能会发生。迫切需要更有效的药物来简化和缩短疗程 应对遵守绝育和治愈所需的必要的漫长疗程的挑战。 在活动性和潜伏性感染期间，已经提出了细菌的一个种群或亚群 进入可逆的非复制状态，对传统抗生素无效。表型抗生素一词 耐受性(药物耐受性)是用来描述抗生素对这些细菌在 不存在基因抗性。在结核分枝杆菌中，有人提出体内药物耐受性可以解释 面对持续感染的长期治疗。因此，结合我们对药物耐受性的理解 而细菌在面对化疗时存活的基础可能是治疗发现的关键 设计针对潜伏感染和持续感染的新策略。 最近，抗生素诱导的活性氧自由基(ROS)被认为是一种 在敏感细胞的抗生素疗效中起重要作用，同时保护抵抗ROS的机制发挥作用 在药物耐受性方面。事实上，这种保护机制在目前所有的体外模型中都有涉及。 药物耐受性。因此，抑制或压倒允许耐药细菌存活的机制 ROS的细胞应激是一种创新的、有前景的策略，可以快速消毒潜伏或持续感染 在这个项目中，我们建议开发新的分析方法来确定以下小分子候选 能够通过破坏耐药结核分枝杆菌的解毒能力而使其灭菌，从而在压力下存活 ROS，或增加细菌中ROS的产生，从而导致它们死亡。我们将使用一种药物模型 耐受性，利用硫脲的能力来淬灭因接触抗生素而产生的羟基自由基， 从而诱导药物耐受性。然后我们将筛选两个独特的、有价值的小分子收藏： 收集我们已经确定的676个分子，这些分子对营养缺乏的结核分枝杆菌具有活性 在其他方面对目前可用的结核病药物具有耐药性，以及独特的10万种以多样性为导向的 布罗德研究所创建的合成分子库。将培养有前途的候选人 获得用于在慢性和潜伏的结核病小鼠模型中进行测试的分子。这部作品将把这部小说 靶向ROS介导的机制的生物学概念与新型靶向持久性和潜伏期 DOS图书馆藏书中的化学，并将利用来自 制药业目前在博德研究所，并在体内测试结核病候选药物方面的专业知识 约翰斯·霍普金斯。

Abstact. Tuberculosis continues to be a disease of significant morbidity and mortality. Complicating its management are its diverse manifestations, ranging from acute disease to latent infection. It is estimated that 1/3 of the world's population has latent TB, resulting in an enormous reservoir from which reactivation to acute disease can occur. More effective drugs are urgently needed to simplify and shorten treatment courses in order to address the challenges of compliance to the requisite lengthy courses required for sterilization and cure. During both active and latent infection, it has been proposed that a population or subpopulation of bacteria enters a reversible non-replicating state, refractory to traditional antibiotics. The term phenotypic antibiotic tolerance (drug tolerance) is used to describe the reduced efficacy of antibiotics against these bacteria in the absence of genotypic resistance. In Mtb, it has been proposed that in vivo drug tolerance could explain the persistence of infection in the face of prolonged therapy. Thus, integrating our understanding of drug tolerance and the basis for bacterial survival in the face of chemotherapy into therapeutic discovery could be key to designing new strategies for targeting latent and persistent infection. Recently, antibiotic-induced reactive oxygen species (ROS) have been recognized as playing an important role in antibiotic efficacy in susceptible cells while mechanisms that protect against ROS play a role in drug tolerance. In fact, such protective mechanisms have been implicated in all current in vitro models of drug tolerance. Thus, inhibiting or overwhelming the mechanisms that allow drug-tolerant bacteria to survive the cellular stress of ROS is an innovative, promising strategy to rapidly sterilize latent or persistent infection In this project, we propose to develop novel assays to identify small molecule candidates which are able to sterilize drug tolerant Mtb bacilli by disrupting their ability to detoxify and thus survive the stress of ROS, or that increase ROS production in bacilli thus contributing to their death. We will use a model of drug tolerance that exploits the ability of thiourea to quench hydroxyl radicals generated by antibiotic exposure, thereby inducing drug tolerance. We will then screen two unique, valuable collections of small molecules: a collection of 676 molecules that we have already identified as having activity against nutrient starved Mtb which are otherwise drug tolerant to currently available TB drugs, and a unique 100,000 diversity oriented synthetic molecule library that has been created at the Broad Institute. Promising candidates will be developed to obtain molecules for testing in chronic and latent mouse models of TB. This work will integrate the novel biological concept of targeting ROS-mediated mechanisms for targeting persistence and latency with novel chemistry in the DOS library collection, and will draw upon drug discovery expertise from leaders in the pharmaceutical industry now at the Broad Institute and expertise in in vivo testing of TB drug candidates at Johns Hopkins.