Understanding The Biosynthesis Of Complex Polyketide Lipid Toxins In Pathogenic Mycobacteria
Funder
National Health and Medical Research Council
Funding Amount
$298,898.00
Summary
Some major infectious diseases such as tuberculosis are caused by bacteria that make very unusual lipids (fats) that can kill human cells or interfere with the human immune system. The aim of this project is to work out how bacteria make these lipids. This knowledge will open up new avenues for treatments to stop bacterial lipid production and prevent disease. There are also potential applications in harnessing the bacterial lipid machinery to make new drugs and a wide range of other chemicals.
Buruli ulcer (BU) is a destructive skin and soft tissue infection that can cause permanent deformity. Australian native possums carry in their guts the bacteria that causes BU and mosquitoes spread BU to people from areas contaminated by possum faeces. A targeted intervention based on screening possum faeces followed by control of mosquitoes in areas where possums and mosquitoes are shown to carry the bacteria will be trialed here, giving public health officials a means to stop this disease.
Investigation Of The Role And Mode Of Action Of Mycolactones And Other Factors In The Pathogenesis Of Buruli Ulcer
Funder
National Health and Medical Research Council
Funding Amount
$509,267.00
Summary
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 Dain ....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.Read moreRead less
Mechanisms Of Repair And Adaptation In The Gastric Mucosa: Roles Of COX-2 And Growth Factors
Funder
National Health and Medical Research Council
Funding Amount
$391,650.00
Summary
The stomach lining is continually threatened by its own acid and by hazards such as bacteria and ingested drugs. The drugs called COX inhibitors, which include aspirin, are widely used for treating arthritis and other inflammatory diseases and for preventing heart attacks and strokes. Despite their value in these conditions, COX inhibitors are responsible for about 5-10,000 hospital admissions annually in Australia due to complications from the side effect of stomach ulcers. A recent advance has ....The stomach lining is continually threatened by its own acid and by hazards such as bacteria and ingested drugs. The drugs called COX inhibitors, which include aspirin, are widely used for treating arthritis and other inflammatory diseases and for preventing heart attacks and strokes. Despite their value in these conditions, COX inhibitors are responsible for about 5-10,000 hospital admissions annually in Australia due to complications from the side effect of stomach ulcers. A recent advance has been the development of a sub-class called COX-2 inhibitors. In a very short time, one of these has become among the most prescribed drugs in Australia. The advantage of the COX-2 inhibitors is that they produce many less stomach ulcers. However, they have only been tested in patients who have not had a recent history of ulcer. Our preliminary experiments, together with some related information from two overseas groups, suggests that COX-2 is useful in the stomach, and is markedly increased around a healing ulcer. Our data suggest that blocking it delays the healing of experimental ulcers. This project aims to understand the roles of COX-2 in the stomach, and to clarify the effects of inhibiting it when the stomach is damaged or threatened. The project will also look for links between COX-2's functions and another protective process we have discovered called 'adaptation'. When anti-inflammatory drugs are given regularly to rats or humans under certain conditions, the stomach develops resistance after a few days so that the damage caused by each subsequent dose is markedly reduced. We have uncovered a number of mechanisms responsible for this during a current NH and MRC grant, and plan to explore some of the leads this work has given. The SIGNIFICANCE of the project is its potential to lead to safer use of anti-inflammatory drugs or eventually to new agents, and its potential to give new knowledge about how the lining of organs such as the stomach protects itself.Read moreRead less
Vaccinating Against Helicobacter Pylori-induced Gastric Cancer
Funder
National Health and Medical Research Council
Funding Amount
$1,088,714.00
Summary
Stomach cancer is the 3rd leading cause of cancer-related deaths. Most stomach cancers result from inflammation due to Helicobacter pylori infection. Most infections are treatable with antibiotics but this does not protect against cancers that develop before infection is diagnosed. Normal vaccine approaches aimed at this infection have been unsuccessful. We have identified a new approach for protecting against stomach cancer by preventing inflammation; this project aims to develop this vaccine.