The mechanistic basis of Artemisia annua activity against Mycobacterium tuberculosis

项目概要/摘要 结核病（TB）很难治疗，部分原因是导致结核病的细菌，结核分枝杆菌， 不容易被抗生素杀死。此外，M.结核病很容易获得高水平的耐药性， 突变。因此，需要六个月或更长时间的多种药物治疗才能完全治愈一个病例。 结核病和预防复发。为了对抗耐药性和缩短治疗方案，需要新的 药物，新的目标，以及对药物相互作用方式的更好理解。黄花蒿是植物 这是抗疟疾药物青蒿素的来源。我们发现A. annua有强大的 对M.青蒿素含量不能完全解释结核病。我们 因此假设A. ANNUA含有一种或多种具有抗分枝杆菌活性的其它化合物。 为了评估这些化合物开发成结核病药物的潜力，我们将（1）确定A。 annua提取物对M.结核病基因表达，（2）选择和测序耐药突变体，（3） 确定青蒿素和A. annua提取物与现有的抗分枝杆菌剂相互作用，和（4）鉴定 和分离物A。一年生化合物负责对M.结核完成本 工作将确定A。单独或与各自组合发挥抗分枝杆菌作用的化合物 其他或青蒿素，并阐明这些化合物的作用机制及其潜力 与现有药物协同作用。因此，拟议的研究将提供所需的基础知识 以鉴定和进一步开发具有治疗潜力的支架。

Project summary/abstract Tuberculosis (TB) is difficult to treat in part because the bacterium that causes it, Mycobacterium tuberculosis, is not easily killed by antibiotics. Furthermore, M. tuberculosis easily acquires high-level drug resistance through mutations. As a consequence, six months or more of multi-drug treatment are required to fully cure a case of TB and prevent relapse. To combat drug resistance and shorten treatment regimens, there is need for new drugs, new targets, and improved understanding of the ways that drugs interact. Artemisia annua L. is a plant that is the source of the antimalarial drug artemisinin. We have found that extracts of A. annua have strong bactericidal activity against M. tuberculosis that cannot be fully explained by their artemisinin content. We therefore hypothesize that A. annua contains one or more additional compounds with antimycobacterial activity. To assess the potential of these compounds for development into TB drugs, we will (1) define the impact of A. annua extracts on M. tuberculosis gene expression, (2) select for and sequence resistant mutants, (3) determine how artemisinin and A. annua extracts interact with existing antimycobacterial agents, and (4) identify and isolate A. annua compounds responsible for bactericidal activity against M. tuberculosis. Completion of this work will identify A. annua compounds that exert antimycobacterial effects alone or in combination with each other or artemisinin, and shed light on the mechanism(s) of action of these compounds as well as their potential to synergize with existing drugs. The proposed studies will therefore provide foundational knowledge needed to identify and further develop scaffolds with therapeutic potential.