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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要世界上三分之一的人口携带传染性结核分枝杆菌 (Mtb)，导致结核病 (TB)。目前结核病的治疗方法并不简单。结核病耐药性药物的产生是由于治疗不足而选择了耐药性，以及人群本身就具有耐药性。系统蒸发散。由于结核病治疗方案艰巨且难以遵循，大约有耐多药结核病 (MDR-TB) 病例 48 万例，利福平耐药结核病 (RR-TB) 病例 10 万例 2015年，耐多药结核病治疗成功率达52%，约15%病例发展为广泛用药耐药结核病 (XDR-TB)，已在 117 个国家发现。多重耐药结核病需要使用至少 5 种药物的混合物治疗两年。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耐药菌株的传播。我们认为 Mtb 胆固醇代谢有助于持续并为具有新作用机制的治疗提供了靶点。我们的研究将促进提供有关 Mtb 氧化应激抵抗机制以及这些机制如何发挥急需的信息 Nisms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能够缩短结核病治疗时间的药物增效剂。 (2) 生化特性分析仅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包含我们增强剂的目标。 (3) 我们将模拟胆固醇分解代谢物之间的代谢流控制 lism 和 ROS 抵抗途径。总而言之，这些研究将确定药物分发的脆弱目标消除结核分枝杆菌持久性和耐药性的覆盖。