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

验证胆固醇介导的结核分枝杆菌对氧化应激的抵抗力作为药物靶标

• 批准号: 9920672
• 负责人: NICOLE S SAMPSON
• 金额: $ 39.38万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-19 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920672
• 关键词: Animal Model; Bioavailable; Biochemical; Catabolism; Chemicals; Cholesterol; Cholesterol Homeostasis; Clinical; Country; Data; Development; Disease; Dose; Drug Targeting; Drug Tolerance; Drug resistance; Enzymes; Extreme drug resistant tuberculosis; Foamy Macrophage; Generations; Genes; Genus Mycobacterium; Goals; Granuloma; Growth; Immune response; Infection; Infectious Agent; Lead; Lipids; Low-Density Lipoproteins; Mediating; Metabolic; Modeling; Molecular; Molecular Target; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; Oxidative Stress; Oxygen; Pathogenicity; Pathway interactions; Patient Monitoring; Pharmaceutical Preparations; Pharmacotherapy; Population; Post-Translational Protein Processing; Propionates; Proteins; Reactive Oxygen Species; Regimen; Regulon; Resistance; Rifampicin resistance; Role; Stress; Structure; Testing; Therapeutic; Time; Toxic effect; Translating; Tuberculosis; Virulent; Work; bactericide; cholesterol analog; cholesterol control; drug development; drug discovery; improved; inhibitor/antagonist; isoniazid; macrophage; mycobacterial; new therapeutic target; novel therapeutics; pathogen; resistant strain; success; targeted treatment; tuberculosis drugs; tuberculosis treatment; uptake

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.

项目摘要 世界上三分之一的人口携带结核分枝杆菌（Mtb）， 导致肺结核（TB）。目前对结核病的治疗并不简单。对结核病的耐药性 药物的产生是由于选择耐药的治疗不足，以及固有的耐药人群， 选择。由于结核病治疗方案的艰巨性和难以遵循， 2010年，48万例耐多药结核病和10万例耐利福平结核病 2015.耐多药结核病的治疗有52%的成功率，约15%的病例发展为广泛的耐药结核病。 耐药结核病（XDR-TB）已在117个国家发现。 耐多药结核病需要用至少5种药物的鸡尾酒治疗两年。新药物 根除持久性和药物耐受人群的作用机制将减少治疗时间， 致命的耐药菌株的传播。我们认为结核分枝杆菌胆固醇代谢有助于持续- 在宿主中的张力，并提出了一个新的作用机制的治疗目标。我们的研究将有助于- 提供了关于结核分枝杆菌抗氧化应激机制的急需信息，以及这些机制是如何发挥作用的。 寄生虫与胆固醇代谢有关。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效剂。(2)我们将描述 一个调节子的功能，只在分枝杆菌病原体编码，我们的初步数据表明， 包含了我们增效剂的目标(3)我们将模拟控制胆固醇分解和代谢之间的代谢物流动， lism和ROS抗性途径。总之，这些研究将确定药物治疗的脆弱目标， 消除Mtb持久性和药物耐受性。