Menaquinone Biosynthesis: A Drug Target in Gram-Positive Bacteria

 描述（由申请人提供）：许多革兰氏阳性菌，包括结核分枝杆菌、单核细胞增生李斯特菌和金黄色葡萄球菌，是对人类痛苦具有重大影响的病原体，并可能在全球范围内造成生物恐怖主义。随着几乎所有病原体的耐药性水平的增加，人们对新药的开发产生了极大的兴趣。世界卫生组织（WHO）公布了一个目标，即到2015年在1期临床试验中有21种新的或重新用途的抗结核药物。实现这一目标将需要大量的努力和资金投入;然而，对抗这些病原体的新药将有助于减少人类的痛苦，并可能应对生物恐怖主义的威胁。上述病原体是专性需氧革兰氏阳性菌，在其电子传递链中利用甲萘醌作为唯一的脂醌。这表明甲基萘醌的合成可能是所有药物的潜在靶点。虽然这里提出的工作适用于大多数革兰氏阳性菌，重点放在M。结核因此，该项目的首要目标是确定有可能进入药物开发管道并有助于实现世卫组织目标的新化合物。我们以前已经证明，甲基萘醌合成是一个可行的“可药物化”的目标，并确定了参与甲基萘醌合成的酶在分枝杆菌，以前是未知的，这也可能提供潜在的新的药物靶点。在这个项目中，我们将通过酶动力学指导的药物化学来改进我们的先导化合物，评估这些新化合物的作用机制，并研究被确定参与分枝杆菌甲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，确定抑制氧化磷酸化各个方面的新药效团，确定以前未知的药物靶点，并显着推进我们对分枝杆菌如何能够调节氧消耗和ATP合成的理解在感染肺部肉芽肿中发现的缺氧条件下。

 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.