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.

项目摘要世界人口的三分之一带有感染剂结核分枝杆菌（MTB）引起结核病（TB）。目前对结核病疾病的治疗并不直接。对结核病的耐药性药物是由于选择抗性的治疗不足以及固有抵抗性的popula-导致的 tions。由于TB治疗的艰巨且难以遵循方案，大约有 480,000例多药耐药结核病（MDR-TB）和100,000例利福平耐药TB（RR-TB） 2015年。MDR-TB的治疗率为52％，大约15％的病例成长为广泛的药物在117个国家 /地区发现了抗性结核病（XDR-TB）。耐多药的结核病需要至少5种药物的鸡尾酒两年来治疗两年。新药与消除持久性和耐药种群的作用机制将减少治疗时间和耐药性抗药性菌株的扩散。我们建议MTB胆固醇代谢有助于persis- 在宿主中，并提出了具有新的作用机理的治疗剂的目标。我们的研究将支持有关MTB中氧化应激抗性机制的急需信息以及这些机制如何 NISM与胆固醇代谢有关。完成后，（1）我们将确定结核病的分子靶标具有缩短结核病治疗时间的能力的药物增强剂。（2）我们将表征生化仅在分枝杆菌病原体中编码的调节量的功能，我们的初步数据建议包含我们的电位器的目标。（3）我们将模拟胆固醇caltabo-之间代谢物流量的控制 lism和ROS抗性途径。综上所述，这些研究将确定弱势药物的靶标消除MTB持久性和药物耐受性的概念。