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Stress-potentiated screening to identify novel inhibitors of M. tuberculosis

应激强化筛选以确定结核分枝杆菌的新型抑制剂

基本信息

批准号：
8500180
负责人：
ROBERT N HUSSON
金额：
$ 20.45万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2014-12-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8500180
关键词：
Address Anti-Bacterial Agents Antibiotics Antitubercular Agents Attenuated Bacteria Cell Culture System Cells Data Directly Observed Therapy Drug Interactions Drug Resistant Tuberculosis Drug resistance Environment Enzymes Generations Goals Granuloma Growth Guidelines HIV Health system Human In Vitro Individual Infection Laboratories Lead Methods Modeling Mycobacterium tuberculosis Natural Immunity Nitrogen Oxidative Stress Oxygen Patients Phagocytes Pharmaceutical Preparations Pharmacotherapy Plague Production Regulation Research Resources Rifampin Stress Superoxides Testing Toxic effect Translating Tuberculosis Virulence World Health Organization acquired immunity antimicrobial bactericide base biological adaptation to stress enzyme activity in vivo inhibitor/antagonist mycobacterial nitrosative stress novel novel strategies pathogen repaired resistant strain response screening small molecule treatment duration tuberculosis drugs tuberculosis treatment

项目摘要

DESCRIPTION (provided by applicant): The goal of this R21 project is develop novel approaches to identify inhibitors of Mycobacterium tuberculosis that will have potent in vivo activity. The hypothesis underlying this proposal is that inhibitors that have increased activity i the setting of oxidative or nitrosative stress will be active during human infection, where these stresses are generated by host phagocytes and function as major antibacterial effectors. The goal of this research will be addressed through two specific aims. First we will develop and perform small molecule screens to identify inhibitors that are active in the presence of oxidative or nitrosative stresses. Second, to examine whether stress-potentiated inhibitors are likely to be active in vivo, we will determine their activity in a human in vitro granuloma model of M. tuberculosis infection. Completion of these aims will provide evidence as to whether inhibitors that are active in the presence of stress, or potentiated by stress, are likely to be good candidates for new anti-tuberculosis drugs. These data will provide the basis for performing large-scale stress- based screens to identify inhibitors that may be developed as candidate new drugs for tuberculosis.

描述（由申请人提供）：这个R21项目的目标是开发新的方法来鉴定具有有效体内活性的结核分枝杆菌抑制剂。这一提议的假设基础是，在氧化或亚硝化应激环境下活性增加的抑制剂在人类感染期间也会活跃，而这些应激是由宿主吞噬细胞产生的，并作为主要的抗菌效应物发挥作用。本研究的目标将通过两个具体目标来解决。首先，我们将开发并执行小分子筛选，以确定在氧化或亚硝化应激存在下具有活性的抑制剂。其次，为了检验应激增强抑制剂是否可能在体内有活性，我们将在体外结核分枝杆菌感染的人类肉芽肿模型中测定它们的活性。这些目标的完成将提供证据，证明在压力存在下是否有活性的抑制剂，或被压力增强的抑制剂，可能是新的抗结核药物的良好候选者。这些数据将为进行大规模的应激筛选提供基础，以确定可能作为结核病候选新药开发的抑制剂。