Investigation of the role and mode of action of mycolactones and other factors in the pathogenesis of Buruli ulcer

溃疡分枝杆菌是一种导致一种非常严重的溃疡性皮肤病的细菌，称为布鲁里溃疡。唯一有效的治疗方法是手术切除受影响的组织，这一过程可能会使受害者终身残疾。布鲁里溃疡在中非和西非的许多国家急剧增加，其原因尚不清楚。布鲁里溃疡病例也出现在澳大利亚南部和北部，在那里这种疾病分别被称为贝恩斯代尔溃疡和丹特里溃疡。溃疡分枝杆菌会产生一种名为分枝杆菌内酯的不同寻常的毒素，这种毒素会杀死人类细胞，并导致免疫抑制。霉菌内酯是一类具有重要药理作用的化合物，包括抗生素、抗肿瘤药物和免疫抑制药物。这个项目的目的是更好地了解霉菌内酯是如何杀死细胞和引起免疫抑制的，并确定溃疡分枝杆菌可能需要的其他部分。我们最近已经确定了溃烂分枝杆菌的完整DNA序列，所以我们现在可以非常密切地观察这种细菌是如何致病的。我们将利用我们对分枝杆菌内酯DNA的知识来对改良的分枝内酯进行基因工程，通过系统地对分枝内酯进行修饰，然后测试修饰化合物的性能，我们将能够识别赋予其毒性和免疫抑制特性的分枝内酯的成分。我们还将测试溃烂分枝杆菌中鉴定出的其他DNA序列的产物是否具有杀死细胞或引起其他可能导致溃疡的生物效应的能力。这个项目的结果将是我们对霉菌内酯和其他因素在导致布鲁里溃疡中的作用的了解，这是非常必要的。这一知识将为开发有效的治疗方法铺平道路，也将为在开发新药物中利用霉菌内酯的生物学特性开辟道路。

Mycobacterium ulcerans is a bacterium that causes a very serious ulcerating skin disease known as Buruli ulcer. The only effective treatment is surgical removal of affected tissue, a process that can leave victims with life-long disabilities. Buruli ulcer has been increasing dramatically in many countries of Central and West Africa for reasons that are not well understood. Cases of Buruli ulcer also occur in the south and north of Australia where the disease is known as Bairnsdale ulcer and Daintree ulcer respectively. M. ulcerans produces an unusual toxin called mycolactone that kills human cells and causes immunosuppression. Mycolactone belongs to a class of compounds that have important pharmaceutical properties and include antibiotic, anti-tumour and immunosuppressive drugs. The aim of this project is to better understand how mycolactone kills cells and causes immunosuppression, and to identify other parts of M. ulcerans that may be required for ulcer formation. We have recently determined the complete DNA sequence of M. ulcerans and so we can now look very closely at how the bacterium causes disease. We will use our knowledge of the mycolactone DNA to genetically engineer modified mycolactones, and by systematically modifying mycolactone and then testing the properties of the modified compounds, we will be able to identify the components of mycolactone that confer its toxic and immunosuppressive properties. We will also test the products from other DNA sequences identified in M. ulcerans for their ability to kill cells or cause other biological effects that may be implicated in causing ulcers. The outcome of this project will be a much needed increase in our understanding of the role of mycolactone and other factors in causing Buruli ulcers. This knowledge will pave the way for developing effective treatments and will also open avenues for exploiting the biological properties of mycolactones in the development of new pharmaceuticals.