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: 7071724
• 负责人: Michael R McNeil
• 金额: $ 87.97万
• 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/7071724
• 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通知的目的不是-AAI-02-023是为了加快研究，导致对潜在的生物恐怖剂MDR-TB的治疗。与当前的结核病药物相比，基于不同目标的新化学疗法是需要准备进行临床试验所需的铅。由于缺乏所需的导线，建议通过开发几种不受当前药物靶向的基本细胞壁合成酶的抑制剂来开发针对MDR-TB的新铅，并在小鼠中有效。 通过筛选具有基于微滴定板的酶测定的化学文库，可以鉴定出抑制三种不同细胞壁合成酶的化合物（其中一些也抑制了结核病的生长）。这些且类似地确定的命中将被改进为高效的酶抑制剂，也将使用“化合物改进”循环对MDR-TB进行活跃。该周期始于对靶向酶（尤其是具有键抑制剂的酶）进行X射线晶体学研究的“复合开发组”，从而开始进行分子建模以设计新的抑制剂，并最终基于该建模并结合了化学多样性，并最终合成了一组基于该建模的化合物。然后，“复合分析组”决定了酶抑制的功效，MIC对MDR-TB分离株的MIC值，体外细胞的毒性，以及根据有必要的小鼠的毒性，干扰素Gamma敲出小鼠的疗效，基本的药代动力学和标准小鼠模型中的效率。化合物分析组的数据传输到化合物开发组，以便可以制定新的进一步精制化合物。每个类别的抑制剂都可以继续周期，直到出现所需特性的化合物或确定特定类型的化合物不太可能成为新药。目前，该循环已准备好从三种必需酶的抑制剂开始。此外，我们还将开发微量滴定板测定和屏幕化学文库，以供四种其他必需的细胞壁生物合成酶进行命中，然后进入细化周期。