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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：
8383145
负责人：
ROBERT N HUSSON
金额：
$ 24.64万
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 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8383145
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 Screening procedure 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 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. PUBLIC HEALTH RELEVANCE: Tuberculosis is difficult to treat, requiring prolonged multi-drug therapy; treatment of drug-resistant tuberculosis, which is increasing globally, is even more challenging. New drugs for tuberculosis treatment are urgently needed to shorten treatment duration and provide better treatment for drug-resistant TB. This project will develop and test new methods to identify inhibitors that may lead to new approaches to treating tuberculosis. !

描述(由申请人提供)：该R21项目的目标是开发新的方法来确定具有有效体内活性的结核分枝杆菌抑制剂。支持这一建议的假设是，在氧化或亚硝化应激的背景下，具有增强活性的抑制物在人类感染期间将是活跃的，这些应激由宿主吞噬细胞产生，并作为主要的抗菌效应物发挥作用。这项研究的目标将通过两个具体目标来实现。首先，我们将开发并进行小分子筛选，以确定在氧化或亚硝化压力下活性的抑制剂。其次，为了检验应激增强抑制物在体内是否可能有效，我们将在人类结核分枝杆菌感染的体外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，证明在压力存在时活跃的或因压力而增强的抑制剂是否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基于压力的筛查提供基础，以确定可能被开发为结核病候选新药的抑制剂。与公共卫生的相关性：结核病很难治疗，需要长期的多种药物治疗；全球范围内耐药结核病的治疗更具挑战性。迫切需要治疗结核病的新药，以缩短疗程，为耐药结核病提供更好的治疗。该项目将开发和测试新的方法，以确定可能导致治疗结核病的新方法的抑制剂。好了！