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。全世界每年约有200万人死于结核病，比任何其他由单一感染源引起的疾病都要多。近年来，由于艾滋病流行和结核病细菌的出现，这种疾病再次出现，而这些细菌并不是现有的抗生素所能杀死的。必须开发新的抗生素来对抗这一全球健康威胁。这需要确定抗生素可以作用于细菌的靶标。一个特别吸引人的目标是细菌的外层。现有的几种抗生素针对的是细菌的外壳，但对细菌外壳的组装方式知之甚少。细菌外壳中的两种相关化合物称为PIM和LAM，它们是结核病细菌所特有的。这些化合物的结构是已知的，而且这些化合物似乎对细菌在人类宿主中的生存至关重要。然而，细菌制造PIM和LAM的机制却知之甚少。我们研究建议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病疗法，可以拯救全球数百万人的生命。

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.