Targets for short-course TB therapy

描述（由申请人提供）：尽管有几种有效的抗生素，结核病（TB）仍然是传染病导致死亡的主要原因之一。结核分枝杆菌感染的治疗是困难的，主要是由于这种生物体的显着能力，坚持尽管数月或数年的抗生素治疗，往往导致不完全灭菌和复发性疾病。治疗不足的必然后果是出现多药耐药菌株，这是更具挑战性的treat.While临床重要性的这一现象不能被夸大，一个机械的理解细菌的持久性在治疗和策略，以更有效地治疗这种感染已被证明是难以捉摸的。我们建议采用两种新的遗传学方法来了解分子水平上的抗生素持久性，并确定代表更有效治疗靶点的细菌途径。首先，我们将采用“转座子位点杂交”，以确定结核分枝杆菌的基因，需要在感染动物的抗生素治疗的持久性。这些信息将用于表征这种细菌在感染期间所采用的抗生素“耐受”状态，并定义协同疗法的新靶点。作为一个平行的方法，我们将开发一个简单的系统，有条件地抑制M的必需基因。结核病，以确定其抑制导致在类似于体内环境的条件下快速细胞死亡的途径。我们希望这两种方法都能深入了解细菌的代谢状态，这种状态是感染期间其显着抗生素耐受性的原因，并确定可以减少治疗结核病所需时间的药物的潜在靶点。短程治疗可以通过改善获得有效治疗的机会、降低结核病的流行率和防止耐药性的迅速出现，对目前的结核病大流行产生巨大影响。结核病仍然是一个祸害，主要是因为目前可用的抗生素只有在服用数月后才有效。我们将采用两种独立的方法来确定可以被新药靶向的细菌途径，以缩短有效治疗的持续时间。短程治疗可以通过使治疗更广泛地提供和降低耐药菌株的出现率来影响全球结核病流行。

DESCRIPTION (provided by applicant): Despite the availability of several effective antibiotics, tuberculosis (TB) remains one of the leading causes of death due to infectious disease. The treatment of Mycobacterium tuberculosis infections is difficult largely due to this organism's remarkable ability to persist in spite of months or years of antibiotic treatment, often resulting in incomplete sterilization and recurrent disease. The inevitable consequence of inadequate therapy is the emergence of multidrug-resistant strains, which are even more challenging to treat. While clinical importance of this phenomenon cannot be overstated, a mechanistic understanding of bacterial persistence during therapy and strategies to treat this infection more effectively has proven elusive. We propose to employ two new genetic methodologies to understand antibiotic persistence at the molecular level, and to identify bacterial pathways that represent targets for a more effective therapeutics. First, we will employ "transposon-site hybridization" to identify mycobacterial genes that are required for persistence during antibiotic treatment of infected animals. This information will be used to characterize the antibiotic "tolerant" state adopted by this bacterium during infection and to define novel targets for synergistic therapies. As a parallel approach, we will develop a facile system for conditionally inhibiting essential genes of M. tuberculosis in order to define pathways whose inhibition results in rapid cell death under conditions similar to the in vivo environment. We expect both of these approaches to provide insight into the metabolic state of the bacterium that is responsible for its remarkable antibiotic tolerance during infection, and to identify potential targets for drugs that could reduce the time required to treat TB. Short-course therapy could have a dramatic effect on the current TB pandemic by improving access to effective treatment, reducing the prevalence of TB, and preventing the rapid emergence of drug resistance. Tuberculosis remains a scourge largely because currently available antibiotics are effective only after many months of administration. We will pursue two independent approaches to identify bacterial pathways that could be targeted by new drugs to shorten the duration of effective treatment. Short-course therapy could impact the worldwide tuberculosis epidemic both by making treatment more widely available and by reducing the rate at which drug-resistant strains emerge.