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：
8032525
负责人：
DEAN C CRICK
金额：
$ 33.06万
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 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8032525
关键词：
Anabolism Antitubercular Agents Area Bacillus anthracis Bioavailable Biological Assay Biological Availability Bioterrorism Catalysis Categories Characteristics Cholesterol Clinical 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 Organism Patients Pharmaceutical Chemistry Pharmaceutical Preparations Property Research Staphylococcus epidermidis Structure-Activity Relationship Testing Toxic effect Transferase Transportation Tuberculosis Vitamin K 2 combat cost design drug development high throughput screening inhibitor/antagonist interest mycobacterial pathogen programs tuberculosis drugs weapons of mass destruction

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）：已鉴定出结核分枝杆菌中甲基萘醌合成（特别是MenA）的有效抑制剂，其也是分枝杆菌生长的有效抑制剂。由于利用甲基萘醌是革兰氏阳性生物体的特征，因此这些化合物对诸如耐甲氧西林金黄色葡萄球菌和表皮葡萄球菌等生物体也具有活性，并且预计对炭疽杆菌和单核细胞增生李斯特氏菌也有效。此处确定为 MenA 抑制剂的化合物最初是作为胆固醇合成抑制剂开发的，因此已知在哺乳动物中具有生物利用度并且具有较低的内在毒性。这些化合物将通过合成药物化学循环进行“复古设计”，然后评估甲基萘醌和细菌生长抑制剂等化合物。这些化合物也将被反选，以降低它们作为胆固醇合成抑制剂的有效性。此外，还将确定 MenA 的催化机制以及参与甲基萘醌合成的替代药物靶点。本申请的具体目的是： 1) 测试假设参与结核分枝杆菌中甲基萘醌合成的 MenA、GrcC1、GrcC2 和 Rv0558 基因的重要性。 2) 设计、合成和测试一类源自氧化角鲨烯环化酶抑制剂的新型抗结核药物。 3) 定义 MenA 催化机制，表征 GrcC1 和 Rv0558 的酶特性，并为那些被证明是必需的酶开发高通量筛选兼容测定法。该研究计划的结果预计对于发现新的先导化合物具有重要意义，这些化合物可以开发成新药来对抗革兰氏阳性 NIAID A、B 和 C 类优先病原体，以及由革兰氏阳性菌引起的新发疾病- 阳性细菌。