Validating cholesterol-mediated Mycobacterium tuberculosis resistance to oxidative stress as a drug target

项目摘要 世界上三分之一的人口携带结核分枝杆菌(Mtb)感染剂 导致结核病(TB)。目前结核病的治疗方法并不简单。对结核病的耐药性 药物的产生来自于没有足够的治疗来选择耐药性，以及来自固有的耐药性人群- 特兹。由于结核病治疗方案的艰辛和困难，大约有 年48万例耐多药结核病(MDR-TB)和10万例利福平耐药结核病(RR-TB) 2015年。耐多药结核病的治疗成功率为52%，约15%的病例发展为广谱药物 耐药结核病(广泛耐药结核病)，已在117个国家发现。 耐多药结核病需要用至少5种药物组成的鸡尾酒疗法治疗两年。新药与 消除持久性和耐药人群的行动机制将减少治疗时间和 强毒力耐药菌株的传播。我们认为Mtb的胆固醇代谢有助于持久-- 为治疗提供了一种新的作用机制。我们的研究将促进- 我们需要了解结核分枝杆菌的氧化应激抵抗机制，以及这些机制是如何发挥作用的。 营养不良与胆固醇新陈代谢有关。完成后，(1)我们将确定结核病的分子靶点 有能力缩短结核病治疗时间的药物增强剂。(2)我们将对生物化学进行表征 只在分枝杆菌病原体中编码的调节子的功能，我们的初步数据表明 含有我们的增强剂的靶标。(3)我们将模拟控制代谢产物在胆固醇代谢酶之间的流动。 LISM和ROS抗性途径。综上所述，这些研究将确定易受药物滥用的目标。 消除结核杆菌持久性和药物耐受性的发现。

Project Summary One third of the world's population carries the infectious agent Mycobacterium tuberculosis (Mtb) that causes tuberculosis (TB). Current treatments for TB disease are not straightforward. Drug resistance to TB drugs results from insufficient treatments that select for resistance, as well as from inherently resistant popula- tions. Because of the arduous and difficult to follow regimen for TB treatment, there were approximately 480,000 cases of multi-drug resistant TB (MDR-TB) and 100,000 cases of rifampicin-resistant TB (RR-TB) in 2015. Treatment of MDR-TB has a 52% success rate, and about 15% of cases develop into extensively-drug resistant TB (XDR-TB), which has been found in 117 countries. Multi-drug resistant TB requires treatment for two years with a cocktail of at least 5 drugs. New drug with mechanisms of action that eradicate persistence and drug tolerant populations will reduce treatment times and the spread of virulent drug resistant strains. We propose that Mtb cholesterol metabolism contributes to persis- tence in the host and presents a target for therapeutics with new mechanisms of action. Our studies will pro- vide much needed information about mechanism of oxidative stress resistance in Mtb and how these mecha- nisms are tied to cholesterol metabolism. Upon completion, (1) we will identify the molecular target of a TB drug potentiator that has the capacity to shorten TB treatment times. (2) We will characterize the biochemical function of a regulon that is only encoded in mycobacterial pathogens, and which our preliminary data suggest contains the target of our potentiators. (3) We will model control of metabolite flow between cholesterol catabo- lism and ROS resistance pathways. Taken together, these studies will identify vulnerable targets for drug dis- covery that eliminates Mtb persistence and drug tolerance.