MDR-TB Drugs: Targeting Cell Wall Synthetic Enzymes

耐多药结核病药物：靶向细胞壁合成酶

• 批准号: 6710418
• 负责人: Michael R McNeil
• 金额: $ 100.08万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-15 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6710418
• 关键词: Mycobacterium tuberculosis; antitubercular agents; bacterial proteins; bioterrorism /chemical warfare; cell wall; drug design /synthesis /production; enzyme inhibitors; multidrug resistance

DESCRIPTION (provided by applicant): A purpose of NIH Notice NOT-AI-02-023 is to expedite research leading to the treatment of MDR-TB, a potential bioterrorism agent. New chemotherapies based on different targets than the present TB drugs are needed, but there is a paucity of the required leads ready for clinical trials. In response to this lack of required leads, it is proposed to develop new leads active against MDR-TB and effective in mice by developing inhibitors of several essential cell wall synthetic enzymes not targeted by current drugs. Compounds that inhibit three different cell wall synthetic enzymes (some of which also inhibit the growth of TB) have been identified by screening a chemical library with microtiter plate based enzyme assays. These and similarly identified hits will be refined into highly effective enzyme inhibitors also active against MDR-TB using a "compound refinement" cycle. The cycle begins with the "compound development group" doing X-ray crystallography studies of the targeted enzymes (especially enzymes with bond inhibitors), proceeding to molecular modeling to design new inhibitors and finally synthesizing a group of compounds based on this modeling and also incorporating chemical diversity. Then the "compound analysis group" determines efficacy of enzyme inhibition, MIC values on a panel of MDR-TB isolates, in vitro cell toxicity, and as warranted, toxicity in mice, efficacy in an interferon gamma knock out mouse, basic pharmacokinetics, and efficacy in a standard mouse model. The data from the compound analysis group is relayed to the compound development group so that a new round of further refined compounds can be prepared. The cycle is continued for each class of inhibitors until compounds with the desired properties emerge or it is determined that a particular class of compounds is unlikely to be yield new drugs. The cycle is presently ready to begin with inhibitors of three essential enzymes; in addition we will develop microtiter plate assays and screen chemical libraries for hits for four additional essential cell wall biosynthetic enzymes which will then enter the refinement cycle.

描述（由申请人提供）：NIH 通知 NOT-AI-02-023 的目的是加快治疗耐多药结核病（一种潜在的生物恐怖分子）的研究。需要基于与现有结核病药物不同靶点的新化疗方法，但可供临床试验所需的先导药物却很少。针对缺乏所需先导化合物的情况，建议通过开发当前药物未针对的几种必需细胞壁合成酶的抑制剂来开发对耐多药结核病具有活性且对小鼠有效的新先导化合物。 通过使用基于酶测定的微量滴定板筛选化学库，已鉴定出抑制三种不同细胞壁合成酶（其中一些还抑制结核病生长）的化合物。这些和类似鉴定的命中将通过“化合物精炼”循环精炼成高效酶抑制剂，对耐多药结核病也有活性。该周期始于“化合物开发小组”对目标酶（特别是具有键抑制剂的酶）进行 X 射线晶体学研究，然后进行分子建模以设计新的抑制剂，最后基于该模型合成一组化合物，并纳入化学多样性。然后，“化合物分析组”确定酶抑制的功效、一组 MDR-TB 分离株的 MIC 值、体外细胞毒性以及必要时的小鼠毒性、干扰素 γ 敲除小鼠的功效、基本药代动力学以及标准小鼠模型中的功效。来自化合物分析小组的数据被转发到化合物开发小组，以便可以制备新一轮的进一步精炼的化合物。对于每一类抑制剂，该循环继续进行，直到出现具有所需特性的化合物，或者确定特定类别的化合物不太可能产生新药。该循环目前已准备好从三种必需酶的抑制剂开始；此外，我们将开发微量滴定板测定法并筛选化学文库，以寻找四种其他必需细胞壁生物合成酶的命中结果，然后将其进入精制循环。