MDR-TB Drugs: Targeting Cell Wall Synthetic Enzymes

描述（由申请人提供）：NIH通知no - ai -02-023的目的是加速导致耐多药结核病治疗的研究，耐多药结核病是一种潜在的生物恐怖主义制剂。需要基于不同靶点的新化疗药物，而不是目前的结核病药物，但是缺乏临床试验所需的线索。针对这一缺乏所需先导物的问题，研究人员建议通过开发几种现有药物无法靶向的基本细胞壁合成酶抑制剂，开发对耐多药结核病有效的新先导物。

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.