Menaquinone Biosynthesis: A Drug Target in Gram-Positive Bacteria

甲基萘醌生物合成：革兰氏阳性细菌中的药物靶点

基本信息

批准号：
9232060
负责人：
DEAN C CRICK
金额：
$ 41.96万
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 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9232060
关键词：
ATP Synthesis Pathway Acids Aerobic Anabolism Bacillus (bacterium)Benzophenones Binding Binding Sites Biochemical Biological Availability Bioterrorism Carbamates Development Diphosphates Drug Targeting Drug resistance Electron Transport Ensure Enzyme Kinetics Enzymes Evaluation Funding Future Generations Genetic Genus Mycobacterium Goals Gram-Positive Bacteria Grant Granuloma Growth Human Hydrophobicity Hypoxia In Vitro Investments Isoprene Lead Listeria monocytogenes Lung Metabolic Microbiology Mycobacterium tuberculosis Oral Organism Organizational Objectives Oxidative Phosphorylation Oxygen Consumption Pharmaceutical Chemistry Pharmacology Phase I Clinical Trials Physiological Process Property Proteins Publishing Resources Side Specificity Staphylococcus aureus Structure-Activity Relationship System Testing Virulence Factors Vitamin K 2 Work World Health Organization base combat cytotoxicity drug candidate drug development improved in vivo inhibitor/antagonist insight interest ionization macrophage mouse model mycobacterial new therapeutic target novel novel therapeutics pathogen pharmacophore piperidine public health relevance tool tuberculosis drugs tuberculosis treatment virtual

项目摘要

DESCRIPTION (provided by applicant): Many Gram-positive bacteria including Mycobacterium tuberculosis, Listeria monocytogenes and Staphylococcus aureus are pathogens with significant impact on human suffering, and potentially, bioterrorism worldwide. With increasing levels of drug resistance in virtually all pathogens there is significant interest n the development of new drugs. The World Health Organization (WHO) published a goal of having 21 new or repurposed anti-tuberculosis drugs in Phase 1 clinical trials by 2015. Reaching this goal will require a tremendous investment in effort and money; however, new drugs to combat these pathogens would help reduce human suffering and potentially counter the threat of bioterrorism. The pathogens mentioned above are obligate aerobic Gram-positives, utilizing menaquinone as the sole lipoquinone in their electron transport chain. This suggests that menaquinone synthesis may present a potential drug target in all. Although the work proposed here is applicable to most Gram-positive organisms, emphasis has been placed on M. tuberculosis. Thus, the overriding goal of this project is to identify new compounds that have the potential for entering the drug development pipeline and helping to meet the WHO goals. We have previously demonstrated that menaquinone synthesis is a viable "druggable" target and identified enzymes involved in menaquinone synthesis in mycobacteria that were previously unknown and, which may also provide potential new drug targets. In this project we will refine our lead compounds via medicinal chemistry guided by enzyme kinetics, evaluate mechanisms of action for these new compounds and study the physiological importance of novel enzymes identified to be involved in mycobacterial menaquinone synthesis. If funded, the project will generate new and improved anti-TB compounds based on our current lead compound, identify new pharmacophores that inhibit various aspects of oxidative phosphorylation, identify previously unknown drug targets and significantly advance our understanding of how mycobacteria are able to regulate oxygen consumption and ATP synthesis in the hypoxic conditions found in the granulomas of infected lungs.

描述（由申请人提供）：许多革兰氏阳性细菌，包括结核分枝杆菌、单核细胞增多性李斯特菌和金黄色葡萄球菌，都是对人类痛苦产生重大影响的病原体，而且随着几乎所有病原体的耐药性水平不断提高，人们对全世界的生物恐怖主义产生了巨大的兴趣。世界卫生组织 (WHO) 公布了 21 种新的或改造后的抗结核药物进入 1 期临床试验的目标。到 2015 年，实现这一目标需要投入大量精力和资金；然而，对抗这些病原体的新药将有助于减少人类痛苦，并可能对抗生物恐怖主义的威胁。尽管这里提出的工作适用于大多数革兰氏阳性生物，但这表明甲基萘醌的合成可能是一个潜在的药物靶点。因此，该项目的首要目标是确定有潜力进入药物开发渠道并有助于实现世界卫生组织目标的新化合物。确定了分枝杆菌中甲基萘醌合成所涉及的酶，这些酶以前是未知的，这也可能提供潜在的新药物靶标。在这个项目中，我们将通过酶动力学指导的药物化学来完善我们的先导化合物，评估其作用机制。这些新化合物并研究被确定参与分枝杆菌甲基萘醌合成的新型酶的生理重要性。如果获得资助，该项目将基于我们目前的先导化合物产生新的和改进的抗结核化合物，识别抑制氧化各个方面的新药效团。磷酸化，识别以前未知的颗粒药物靶点，并显着增进我们对分枝杆菌如何能够在受感染肺部肿瘤中发现的缺氧条件下调节耗氧量和 ATP 合成的理解。