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细菌，导致非常严重的溃疡性皮肤病称为布鲁里溃疡。唯一有效的治疗方法是手术切除受影响的组织，这一过程可能使受害者终身残疾。布鲁里溃疡在中非和西非许多国家急剧增加，原因尚不清楚。布鲁里溃疡的病例也发生在澳大利亚的南部和北部，这种疾病分别被称为Bairnsdale溃疡和Daintree溃疡。M.溃疡病产生一种称为霉菌内酯的不寻常毒素，这种毒素杀死人体细胞并引起免疫抑制。菌内酯属于一类具有重要药物特性的化合物，包括抗生素、抗肿瘤和免疫抑制药物。该项目的目的是更好地了解菌内酯如何杀死细胞并引起免疫抑制，并确定M。溃疡形成可能需要的溃疡。我们最近测定了M.所以我们现在可以仔细观察这种细菌是如何致病的。我们将利用我们对真菌内酯DNA的了解来遗传工程改造真菌内酯，通过系统地修饰真菌内酯，然后测试修饰化合物的性质，我们将能够鉴定赋予其毒性和免疫抑制性质的真菌内酯组分。我们还将测试M中鉴定的其他DNA序列的产物。溃疡病是因为它们能够杀死细胞或引起可能与引起溃疡有关的其他生物学效应。该项目的结果将是我们对分枝杆菌内酯和其他因素在引起布鲁里溃疡中的作用的理解的迫切需要的增加。这些知识将为开发有效的治疗方法铺平道路，也将为开发新药物中利用真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.