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

描述（由申请人提供）：该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。该提议的假设是，在氧化或亚硝化应激的情况下具有增加的活性的抑制剂在人类感染期间将是活性的，其中这些应激由宿主吞噬细胞产生并作为主要的抗菌效应物起作用。这项研究的目标将通过两个具体目标来实现。首先，我们将开发和进行小分子筛选，以确定在氧化或亚硝化应激存在下具有活性的抑制剂。第二，为了检验应激增强抑制剂是否可能在体内有活性，我们将在人体外M.肺结核感染。这些目标的完成将提供证据，是否抑制剂，是积极的存在下的压力，或加强压力，可能是新的抗结核药物的良好候选人。这些数据将为进行大规模的基于压力的筛选提供基础，以识别可能被开发为结核病候选新药的抑制剂。 公共卫生相关性：结核病很难治疗，需要长期的多种药物治疗;耐药结核病在全球范围内不断增加，其治疗更具挑战性。迫切需要结核病治疗新药，以缩短治疗时间，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。!

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. !