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

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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.