Genetic and Biochemical Analysis of the PIM/LAM biosynthetic pathway in Mycobacteria.

结核病是人类历史上最具破坏性的疾病之一。结核病每年在全世界造成大约200万人死亡，比任何其他由单一传染性病原体引起的疾病都要多。近年来，由于艾滋病的流行和目前可用的抗生素不能杀死的结核菌的出现，这种疾病重新出现。必须开发新的抗生素来应对这一全球健康威胁。这需要确定抗生素可以作用的细菌靶点。一个特别有吸引力的目标是细菌的外壳。几种现有的抗生素靶向细菌外壳，但对外壳组装的方式知之甚少。细菌外壳中的两种相关化合物是结核菌特有的，称为PIM和LAM。这些化合物的结构是已知的，并且这些化合物似乎是细菌在人类宿主中生存所必需的。然而，细菌制造PIM和LAM的机制知之甚少。我们研究计划的目的是更好地了解这些化合物的制造过程。如果这一过程可以被抗生素阻断，那么这就代表了一种潜在的抗结核治疗方法，可以挽救全世界数百万人的生命。

Tuberculosis (TB) is one of the most devastating diseases in human history. TB kills approximately two millions people each year worldwide, more than any other disease caused by a single infectious agent. The disease has re-emerged in recent years due to the AIDS epidemic and the appearance of TB bacteria that are not killed by currently available antibiotics. New antibiotics must be developed to combat this global health threat. This requires the identification of targets on the bacteria on which antibiotics can act. One particularly attractive target is the outer coat of the bacterium. Several existing antibiotics target the bacterial coat, yet the ways in which coat is assembled are poorly understood. Two related compounds in the bacterial coat, and unique to TB bacteria, are called PIMs and LAMs. The structures of these compounds are known, and the compounds appear to be essential for the survival of the bacteria in the human host. However, the mechanisms by which PIMs and LAMs are made by the bacteria are very poorly understood. The aim of our research proposal is to better understand the process by which these compounds are made. If this process can be blocked by an antibiotic, then this represents a potential anti-TB therapy which could save millions of lives worldwide.