Menaquinone biosynthesis:a drug target in Gram-positive bacteria

甲萘醌生物合成：革兰氏阳性菌的药物靶点

基本信息

批准号：
7373343
负责人：
DEAN C CRICK
金额：
$ 22.14万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-06-15 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7373343
关键词：
Anabolism Antitubercular Agents Area Bacillus anthracis Bioavailable Biological Assay Biological Availability Bioterrorism Catalysis Categories Characteristics Cholesterol Class Clinical Compatible Country Developed Countries Development Diagnosis Disease Drug Delivery Systems Drug Resistant Tuberculosis Drug resistance Effectiveness Enzymes Evaluation Food Supply Genes Gram-Positive Bacteria Growth Growth Inhibitors Incidence Individual Lanosterol synthase Lead Listeria monocytogenes Mammals Methicillin Resistance Multi-Drug Resistance Multiple drug resistant Mycobacteria Tuberculosis Mycobacterium tuberculosis National Institute of Allergy and Infectious Disease Nerve Numbers Organism Patients Pharmaceutical Chemistry Pharmaceutical Preparations Property Research Staphylococcus epidermidis Structure-Activity Relationship Testing Toxic effect Transferase Transportation Tuberculosis Vitamin K 2 cost design drug development high throughput screening inhibitor/antagonist interest mycobacterial pathogen programs tuberculosis drugs

项目摘要

DESCRIPTION (provided by applicant): Potent inhibitors of menaquinone synthesis (specifically MenA) in M. tuberculosis have been identified, which are also effective inhibitors of mycobacterial growth. Since utilization of menaquinone is a characteristic of Gram-positive organisms, these compounds are also active against organisms such as methicillin resistant Stapylococcus aureus and Staphylococcus epidermidis, and are expected to be effective against Bacillus anthracis and Listeria monocytogenes as well. The compounds identified as MenA inhibitors here, were first developed as cholesterol synthesis inhibitors and, as such, are known to be bioavailable in mammals and to have low intrinsic toxicity. These compounds will be "retro-designed" via cycle of synthetic medicinal chemistry followed by evaluation of compounds as menaquinone, and bacterial growth inhibitors. The compounds will also be counter-selected to reduce their effectiveness as cholesterol synthesis inhibitors. In addition, the mechanism of catalysis of MenA and alternative drug targets involved in menaquinone synthesis will be identified. The Specific Aims of this application are to: 1) test MenA, GrcC1, GrcC2 and Rv0558 genes hypothesized to participate in menaquinone synthesis in M. tuberculosis, for essentiality. 2) Design, synthesize and test a new class of anti-tuberculosis agents derived from an oxidosqualene cyclase inhibitor. 3) Define the mechanism of MenA catalysis, characterize the enzymatic properties of GrcC1 and Rv0558 and develop high-throughput screening compatible assays for those enzymes shown to be essential. The results of this research program are expected to be of significance in terms of discovering new lead compounds that can be developed into new drugs to combat Gram-positive NIAID category A, B and C priority pathogens, as well as, emerging diseases caused by Gram-positive bacteria.

描述（由申请人提供）：已经鉴定出了结核分枝杆菌中甲喹酮合成（特别是MENA）的有效抑制剂，这也是分枝杆菌生长的有效抑制剂。由于甲酸苯丙胺的利用是革兰氏阳性生物的特征，因此这些化合物也对诸如耐甲氧西林的金黄色甲雷甲烷和表皮葡萄球菌等有机体有效，并且预计将有效抗贫血和licteracis猫和李斯特氏菌。这里鉴定为MENA抑制剂的化合物首先是作为胆固醇合成抑制剂开发的，因此，已知在哺乳动物中可生物利用，并且内在毒性较低。这些化合物将通过合成药物化学的循环“重新设计”，然后评估化合物为甲苯胺酮和细菌生长抑制剂。这些化合物还将进行对抗选择，以降低其作为胆固醇合成抑制剂的有效性。此外，还将确定MENA催化和参与梅纳金酮合成的替代药物靶标的机制。该应用的具体目的是：1）测试MENA，GRCC1，GRCC2和RV0558基因，假设参与结核分枝杆菌中的Menaquinone合成。 2）设计，合成和测试一类新的源自氧化盐环溶栓酶抑制剂的抗结产剂。 3）定义北非催化的机制，表征GRCC1和RV0558的酶促特性，并为这些酶开发高通量筛选兼容的测定法。预计该研究计划的结果将在发现新的铅化合物方面具有显着性 - 阳性细菌。