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Exploiting metabolic toxicities to identify compounds that inhibit cholesterol metabolism in M. Tuberculosis

利用代谢毒性来识别抑制结核分枝杆菌胆固醇代谢的化合物

基本信息

批准号：
9241338
负责人：
Brian C VanderVen
金额：
$ 38.75万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-15 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9241338
关键词：
Alpha Cell Animal Model Anticholesteremic Agents Bacteria Biological Assay Catabolism Cells Cessation of life Chemicals Cholesterol Cholesterol Homeostasis Collection Complex Disease Drug Targeting Economics Energy Supply Engineering Enzymes Epidemic Genetic Growth Health Human Immune response Incidence Infection Lead Libraries Mass Spectrum Analysis Metabolic Molecular Molecular Target Mycobacterium tuberculosis Natural Products Nutrient Pathogenesis Pathway interactions Pharmaceutical Preparations Process Regimen Reporter Research Research Personnel Signal Transduction Structure of parenchyma of lung Therapeutic Toxic effect Tuberculosis Universities Validation assay development base cytotoxicity drug development experimental study extensive drug resistance genetic analysis genetic approach high throughput screening improved in vitro Assay inhibitor/antagonist innovation insight macrophage mutant novel novel therapeutics pressure public health relevance resistant strain response screening small molecule statistics success tool tuberculosis drugs

项目摘要

DESCRIPTION (provided by applicant): Tuberculosis (TB) is a lasting global epidemic that claims ~1.5 million human lives annually. Mycobacterium tuberculosis (Mtb) is the causative agent of TB and this bacterium establishes long term infections by surviving within macrophages and manipulating the host immune response. Within lung tissue Mtb can persist for decades sequestered away from the pressures of the host immune response. During this persistent infection Mtb solely utilizes host-derived nutrients for survival. Mtb has the ability t utilize host-derived cholesterol during an infection to supply energy producing and/or biosynthetic pathways. Therefore, inhibition of cholesterol catabolism may be a weakness that can be exploited for discovery of new anti-Mtb drugs. For this project we will develop a cell-based assay suitable for HTS that can identify inhibitors of cholesterol catabolism in Mtb. Aim 1: we will develop a robust chemical-suppressor HTS assay 384-well format using the Mtb Icl1 strain. Aim 2: we will complete a pilot HTS and validate hits from the screen. Aim 3: will focus on identifying the enzyme targets of the HTS hits. These studies will yield a HTS ready assay and provide "proof of principle" that our approach can identify selective inhibitors of cholesterol catabolism in Mtb.

描述（由申请人提供）：结核病 (TB) 是一种持久的全球流行病，每年夺去约 150 万人的生命。结核分枝杆菌 (Mtb) 是结核病的病原体，这种细菌通过在巨噬细胞内存活并操纵宿主免疫反应来建立长期感染。在肺组织内，结核分枝杆菌可以在远离宿主免疫反应压力的情况下持续存在数十年。在这种持续感染期间，结核分枝杆菌仅利用宿主来源的营养物质来生存。 Mtb 能够在感染期间利用宿主衍生的胆固醇来提供能量产生和/或生物合成途径。因此，抑制胆固醇分解代谢可能是一个弱点，可用于发现新的抗结核分枝杆菌药物。对于这个项目，我们将开发一种适用于 HTS 的基于细胞的检测方法，可以识别 Mtb 中胆固醇分解代谢的抑制剂。目标 1：我们将使用 Mtb Icl1 菌株开发一种强大的化学抑制 HTS 测定 384 孔格式。目标 2：我们将完成试点 HTS 并验证屏幕上的点击。目标3：将重点识别 HTS 命中的酶靶标。这些研究将产生 HTS 就绪检测，并提供“原理证明”，证明我们的方法可以识别 Mtb 中胆固醇分解代谢的选择性抑制剂。