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

结核分枝杆菌毒力因子分枝杆菌素 T 的生物合成。

• 批准号: nhmrc : 143031
• 负责人: Prof James De Voss
• 金额: $ 14.1万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2002
• 资助国家: 澳大利亚
• 起止时间: 2002-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/biosynthesis-mycobactin-t-mycobacterium-tuberculosis/98373
• 关键词: biosynthesis; Mycobactin; virulence; factor; Mycobacterium

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.

结核分枝杆菌是结核病的病原体。药物异烟肼导致结核病死亡率显著和持续下降。这导致1988年在医学文献中将其描述为一种正在消失的疾病，现在相当容易治疗。然而，艾滋病毒的出现和耐多药结核分支杆菌的迅速崛起导致了戏剧性的变化。艾滋病毒感染者罹患活动性结核病的风险为每年7%，而具有免疫能力的人一生的风险为10%。同样，在包括东南亚在内的许多地区，结核分枝杆菌耐药菌株的流行率超过5%。分枝杆菌感染被认为是世界范围内发病率和死亡率的主要原因，世卫组织估计，未来十年将有3000万人死于这些感染。显然，需要新的药物来对抗这种微生物日益增长的威胁。这个项目的目的是详细说明结核分枝杆菌产生Mycobactin T的独特代谢途径，Mycobactin T对这种生物的毒力至关重要。Mycobactin T帮助细菌获得铁，这是一种重要的营养物质。这些因素使真菌作用途径成为理想的药物靶点，对其生物化学的了解对于最终利用其干预结核分枝杆菌感染至关重要。我们假设它可能已经提供了一种临床上使用的抗结核药物对氨基水杨酸盐(PAS)的未知作用部位。该项目将：i)充分定义mycobactin T的结构；ii)克隆并高效表达催化mycobactin形成的前三步的关键基因；iii)纯化过度表达的蛋白质并对其生化功能进行鉴定；iv)研究Pas与该抗分枝杆菌药物可能靶向的蛋白质之间的相互作用。这项工作的结果将为未来抗结核药物的开发提供依据。