Anti MDR-TB MICs and Cytotoxicity of New Compounds

新化合物的抗耐多药结核病 MIC 和细胞毒性

• 批准号: 6735405
• 负责人: DELPHI CHATTERJEE
• 金额: $ 12.52万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6735405
• 关键词: Mycobacterium tuberculosis; antitubercular agents; bacterial proteins; biomedical facility; bioterrorism /chemical warfare; cell line; cell wall; cytotoxicity; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; multidrug resistance

This Core is a service for the PO1 entitled "MDR-TB drugs: Targeting Cell Wall synthesis enzymes". The core is designed to screen the compounds generated by the =Compound Development Module", which include Project 1 and Project 2 by Dr. Lee and Dr. Naismith, respectively, and also from the "Priming the Refinement Cycle Module", specifically interacting with Dr. McNeil, Project 3. We will obtain the MIC value against MDR-TB for two to three thousand compounds per annum using two adeptly defined MIC methods, primarily the microplate Alamar blue method and secondly the radiometric BACTEC 460TB method to confirm the MIC. Compounds exhibiting good MIC values will be tested for bactericidal activity using the time-kill method. The compounds that present efficient MIC values will undergo further for cytotoxicity studies in mammalian cell lines to obtain the IC50 values, the concentration causing 50% loss of mammalian cell viability. Cytotoxicity assays will be performed in Vero cell lines and, as appropriate, in tumor-derived (HepG2) cell lines. The Compounds with selective index (MIC/IC50) higher than 10 will be considered "defined hits" and will be sent forward to Core B for studies in the animal model. The information gleaned in this Core will be supplied back to Drs. Naismith and Lee of the "Compound Development Module" to enable the synthesis of better compounds.

该核心是为 PO1 提供的一项名为“MDR-TB 药物：靶向细胞壁合成酶”的服务。核心旨在筛选由“化合物开发模块”生成的化合物，其中包括分别由 Lee 博士和 Naismith 博士设计的项目 1 和项目 2，以及来自“启动精炼循环模块”，特别是与 McNeil 博士互动的项目 3。我们将获得针对 MDR-TB 的 MIC 值，为两到三千 每年使用两种适当定义的 MIC 方法（主要是微孔板 Alamar 蓝方法，其次是放射性 BACTEC 460TB 方法来确认 MIC）对化合物进行检测。将使用时间杀灭方法测试表现出良好 MIC 值的化合物的杀菌活性。 具有有效 MIC 值的化合物将在哺乳动物细胞系中进行进一步的细胞毒性研究，以获得 IC50 值，该浓度会导致哺乳动物细胞活力丧失 50%。细胞毒性测定将在 Vero 细胞系中进行，并酌情在肿瘤衍生 (HepG2) 细胞系中进行。选择性指数 (MIC/IC50) 高于 10 的化合物将被视为“确定的命中”，并将被发送至核心 B 进行研究 动物模型。在此核心中收集的信息将提供给 Drs。 Naismith 和 Lee 的“化合物开发模块”能够合成更好的化合物。