The biosynthesis of Mycobactin T, a virulence factor from Mycobacterium tuberculosis.

结核分枝杆菌是结核病的病原体。药物异烟肼导致肺结核死亡率大幅持续下降。这导致它在1988年的医学文献中被描述为一种正在消失的疾病，现在相当容易治疗。结核病导致了巨大的变化。艾滋病毒感染者发展为活动性结核病的风险为每年7%，而免疫功能正常者的终生风险为10%。同样，耐药菌株的流行M。结核病在包括东南亚在内的许多地区超过5%。分枝杆菌感染被认为是全世界发病率和死亡率的主要原因，世卫组织估计，在今后十年中，将有3 000万人死于这些感染。显然，需要新的药物来对抗这种有机体日益增长的威胁。本项目的目的是详细的M独特的代谢途径。结核杆菌产生分枝杆菌素T，这对这种生物的毒力至关重要。Mycobactin T帮助细菌获得铁，这是一种必需的营养素。这些因素使分枝杆菌作用途径成为理想的药物靶点，了解其生物化学对于最终利用其干预M。肺结核感染。我们假设，它可能已经提供了一个未知的网站的作用，临床上使用的抗结核药物对氨基水杨酸（PAS）。该项目将i）完全确定分枝杆菌素T的结构; ii）克隆和过表达催化分枝杆菌素形成的前三个步骤的关键基因; iii）纯化和纯化过表达的蛋白质的生化功能; iv）检测PAS与可能被这种抗分枝杆菌剂靶向的蛋白质的相互作用。本工作的结果将为今后抗结核药物的开发提供依据。

Mycobacterium tuberculosis is the causative agent of tuberculosis. The drug isoniazid led to a dramatic and sustained decline in mortality due to tuberculosis. This led to it being described in medical literature in 1988 as a disappearing disease which was now fairly easy to treat. However, the advent of HIV and the rapid rise of multidrug resistant M. tuberculosis led to dramatic changes. The risk that an HIV infected individual will develop active tuberculosis is 7% per year, compared to a lifetime risk of 10% for an immunocompetent person. Similarly, the prevalence of drug resistant strains of M. tuberculosis is over 5% in many regions, including SE asia. Mycobacterial infections are regarded as the leading cause of morbidity and mortality world wide and WHO estimates that 30 million deaths will occur in the next decade due to these infections. Clearly, new drugs are required to combat the rising menace of this organism. The aim of this project is to detail the unique metabolic pathways in M. tuberculosis that produce Mycobactin T, essential to the virulence of this organism. Mycobactin T helps the bacteria obtain iron, an essential nutrient. These factors make the mycobaction pathway an ideal drug target and an understanding of its biochemistry is essential to its eventual exploitation for intervention in M. tuberculosis infections. We hypothesise that it may already provide the unknown site of action of a clinically employed, antituberculosis drug para-aminosalicylate (PAS). This project will i) fully define the structure of mycobactin T; ii) clone and overexpress key genes which catalyse the first three steps of mycobactin formation; iii) purify and characterise the overexpressed proteins with respect to their biochemical function; iv) examine the interaction of PAS with the proteins likely to be targeted by this antimycobacterial agent. The results of this work will provide the basis for the development of future anti-tuberculosis drugs.