Outer Membrane Proteins Of Leptospira; Role In Immunity And Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$88,500.00
Summary
Leptospirosis is a significant cause of death in tropical regions of the world. Recent outbreaks in Nicaragua and Brazil are timely reminders of the seriousness of disease caused by the Leptospira bacteria. In these outbreaks >10% of people developing the disease did not recover. Spread of the disease does not occur from person to person, but rather from animal to human. Leptospira are shed from infected animals via the urine; human infection may occur through contact with infected urine or u ....Leptospirosis is a significant cause of death in tropical regions of the world. Recent outbreaks in Nicaragua and Brazil are timely reminders of the seriousness of disease caused by the Leptospira bacteria. In these outbreaks >10% of people developing the disease did not recover. Spread of the disease does not occur from person to person, but rather from animal to human. Leptospira are shed from infected animals via the urine; human infection may occur through contact with infected urine or urine contaminated materials. In Australia, leptospirosis is an occupational hazard with dairy farmers, pig handlers, banana pickers and abattoir workers being those most at risk. A recent and alarming development is the emergence of new risk groups associated with certain leisure activities. For example, in the USA three triathletes died from leptospirosis and it was subsequently determined that the source of infection was contaminated swimming water. This project will investigate aspects of the development of disease and immunity during infection by Leptospira. This will be achieved by analysing the set of proteins located on the surface of the bacterium. These proteins play a key role in the development of disease. Using state of the art technology, each of the proteins will be purified and identified. This will enable experiments that will enhance our understanding of the development of disease at a molecular level.Read moreRead less
Molecular Genetics And Evolution Of Antibiotic Resistant Staphylococci
Funder
National Health and Medical Research Council
Funding Amount
$437,545.00
Summary
Potentially life-threatening infections caused by Staphylococcus aureus bacteria, commonly known as Golden Staph, often arise as complications in patients within hospitals. These infections compromise the health of the patient and jeopardise their recovery from the condition for which they were initially admitted, which significantly increases healthcare costs. Hospital-acquired infections caused by Golden Staph are a major problem in Australia and globally. The problem is largely due to the pre ....Potentially life-threatening infections caused by Staphylococcus aureus bacteria, commonly known as Golden Staph, often arise as complications in patients within hospitals. These infections compromise the health of the patient and jeopardise their recovery from the condition for which they were initially admitted, which significantly increases healthcare costs. Hospital-acquired infections caused by Golden Staph are a major problem in Australia and globally. The problem is largely due to the presence in hospitals of strains that have become resistant to most clinically-useful antibiotics and are therefore very difficult to eradicate. This research project will reveal detailed information about strains of Golden Staph that are currently prevalent in hospitals in Australia, USA, Europe, and South East Asia. It will also provide important insights into the mechanisms that enable this organism to become resistant so readily, and identify factors that promote the development of resistant strains. The results of this research project will lead to improved methods for the characterisation of clinical strains and the monitoring of antibiotic resistance. The findings will also be of relevance to other types of antibiotic resistant bacteria. Most importantly, the application of knowledge arising from these studies has potential to minimise the emergence of strains that are even more resistant, thereby extending the effectiveness of existing and future antibiotics. The design and implementation of strategies to limit the proliferation of resistant bacteria are essential if we are to avoid a scenario similar to that prior to the introduction of antibiotics, when serious infectious diseases were often untreatable.Read moreRead less
Genetics And Biochemistry Of Biosynthesis Of The Cell Wall Of Mycobacteria
Funder
National Health and Medical Research Council
Funding Amount
$260,831.00
Summary
Mycobacteria commolnly cause human disease. The major killer in the group is Mycobacterium tuberculosis which annually causes millions of deaths from tuberculosis (TB) worldwide. Another pathogen from this group is Mycobacterium avium which often infects immunosuppressed people such as those with advanced HIV-AIDS. Mycobacteria have evolved a specialised wall that surrounds their cells which protects them from chemical attack from antibiotics and helps them to establish infections. The major ant ....Mycobacteria commolnly cause human disease. The major killer in the group is Mycobacterium tuberculosis which annually causes millions of deaths from tuberculosis (TB) worldwide. Another pathogen from this group is Mycobacterium avium which often infects immunosuppressed people such as those with advanced HIV-AIDS. Mycobacteria have evolved a specialised wall that surrounds their cells which protects them from chemical attack from antibiotics and helps them to establish infections. The major antibiotic used for TB stops cells from synthesising the protective layer thereby making them very vulnerable to human immune defences. Unfortunately, resistance to this antibiotic is common and new antibiotics are needed to treat mycobacterial infections. We are studying how mycobacteria make the cell wall and are looking for key steps where new drugs might be able to inhibit the process. Our approach is to inactivate genes in the mycobacteria that make the enzymes which control cell wall synthesis. The gene inactivation results in crippled mycobacteria that are unable to make proper cell walls. We analyse the cell wall changes that gene inactivation cause studying the chemical composition of the cell. This helps to identify the steps in cell wall biosynthesis and each step becomes a potential target for new drugs. Each of the weaken mycobacteria can be tested to see how well they can resist antibiotics and to see if they can survive host defences. In this way we can identify which components of the cell wall are critical for them to establish infections and resist antibiotic treatments. Enzymes that participate in the synthesis of such components are prime targets for us to concentrate on to design new antibiotics.Read moreRead less
Role Of Regulatory Genes In The Gastrointestinal Pathogen, Clostridium Difficile
Funder
National Health and Medical Research Council
Funding Amount
$287,036.00
Summary
When patients are treated in hospital with antibiotics they sometimes develop chronic diarrhoea or colitis syndromes that are very difficult and expensive to treat. This project involves the analysis of the bacterium that generally causes these gastrointestinal diseases. We know that this microorganism is present in the hospital environment and that it produces potent protein toxins that are responsible for these diseases but we know little about the actual disease process. In most bacteria that ....When patients are treated in hospital with antibiotics they sometimes develop chronic diarrhoea or colitis syndromes that are very difficult and expensive to treat. This project involves the analysis of the bacterium that generally causes these gastrointestinal diseases. We know that this microorganism is present in the hospital environment and that it produces potent protein toxins that are responsible for these diseases but we know little about the actual disease process. In most bacteria that cause disease there are regulatory networks that control the expression of the genes responsible for the disease process. In this project, we aim to develop an understanding of how these regulatory networks operate in this particular bacterium. The latest techniques of molecular biology will be used to investigate several specific regulatory genes at the functional level. Since the entire DNA sequence of this bacterium is now known we will also use a broader research approach that makes use of this knowledge to examine all of potential regulatory networks that exist in this bacterium. Finally, we will develop new methods for the genetic analysis of the causative bacterium so that we will be better able to elucidate the role of specific genes in the disease process. By understanding how this bacterium controls the production of the proteins that interact with human intestinal cells to cause disease we hope to be able to prevent such diseases from occurring. The successful completion of the project therefore will make a major contribution to the development of improved methods for the control and treatment of these chromic diarrhoea and colitis syndromes.Read moreRead less
Unified Model For Group A Streptococcal Invasive Disease Initiation.
Funder
National Health and Medical Research Council
Funding Amount
$605,221.00
Summary
Streptococcus pyogenes (group A streptococcus; GAS) is a bacterium that causes human skin and throat infections as well as highly invasive diseases including necrotising fasciitis and streptococcal toxic shock-like syndrome. We have recently discovered the trigger mechanism for GAS invasive disease. We hypothesise that the initial host response at the site of infection selects for a GAS invasive phenotype. We propose to examine the chain of events which result in tissue invasion in order to unde ....Streptococcus pyogenes (group A streptococcus; GAS) is a bacterium that causes human skin and throat infections as well as highly invasive diseases including necrotising fasciitis and streptococcal toxic shock-like syndrome. We have recently discovered the trigger mechanism for GAS invasive disease. We hypothesise that the initial host response at the site of infection selects for a GAS invasive phenotype. We propose to examine the chain of events which result in tissue invasion in order to understand these disease processes and allow the development of future therapeutic interventions.Read moreRead less
Multidrug Resistance Regulatory Protein QacR From Staphylococcus Aureus
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
One of the most significant mechanisms of drug resistance is the export of antibiotics and other chemotherapeutic drugs from the cell. Drug export systems are an important medical problem due to their frequent occurrence in bacteria and parasites which cause human disease and in human cancer cells. Proteins which recognise and export a broad range of drugs from a cell are called multidrug efflux pumps. These multidrug efflux systems present a serious threat to patient care and to successful ther ....One of the most significant mechanisms of drug resistance is the export of antibiotics and other chemotherapeutic drugs from the cell. Drug export systems are an important medical problem due to their frequent occurrence in bacteria and parasites which cause human disease and in human cancer cells. Proteins which recognise and export a broad range of drugs from a cell are called multidrug efflux pumps. These multidrug efflux systems present a serious threat to patient care and to successful therapy, since the ability to produce a single protein simultaneously renders the cell or organism resistant to several different drugs. Strains of the bacterial pathogen Staphylococcus aureus or Golden Staph, which are endemic in hospitals world-wide, contain an example of such a multidrug exporter, the QacA multidrug efflux pump, which exports at least 30 different antimicrobial compounds, including antiseptics and disinfectants. Production of this protein is regulated by a sensor protein, QacR, which detects the presence of a number of these antimicrobial compounds. To understand how the QacR sensor protein can recognise such a wide variety of compounds, we will identify and structurally characterise the regions of the QacR multidrug regulatory protein which bind these compounds. Additionally, we will examine the means by which QacR regulates the production of the QacA pump protein. This project will provide fundamental knowledge that will not only help with understanding the important process of multidrug resistance but will also enable the rational design of more effective antibacterial compounds that either block or evade these multidrug efflux systems.Read moreRead less
Identification And Analysis Of Novel Replication Initiation Factors In Staphylococcus Aureus
Funder
National Health and Medical Research Council
Funding Amount
$311,789.00
Summary
Multi-drug resistant Golden staph is a serious medical problem around the world because strains are often resistant to commonly used treatments; new drugs are therefore urgently required. DNA replication is a fundamental process that is essential for the survival of all cellular organisms. This project aims to identify and characterise novel factors involved in DNA replication in Golden staph, which represent potential drug targets.
Role Of Bacteriophage-encoded Streptodornase In Invasive Disease Caused By Diverse Group A Streptococcal M Serotypes.
Funder
National Health and Medical Research Council
Funding Amount
$832,544.00
Summary
Streptococcus pyogenes (group A streptococcus, GAS) is estimated to cause ~700 million cases of self-limited throat or skin infection each year worldwide. Invasive GAS disease occurs in approximately 1-1000 cases, with associated mortality of 25%. We have recently discovered that a viral infection can reprogram GAS for invasive disease propensity. We will investigate whether this phenomenon is widespread, in order to understand this process and develop future therapeutics.
Pathogenomics: New Ways To Exploit Genome Sequence Data From Pathogenic Bacteria.
Funder
National Health and Medical Research Council
Funding Amount
$547,372.00
Summary
Bacterial pathogens are locked in an evolutionary battle of survival with their eukaryote hosts. The rapidly evolving genes of medically-important pathogens are generally those required for adaptation to the human host. This project aims to exploit the abundance of available bacterial genome sequences to predict rapid evolution in bacterial pathogens using computational methods. The protein products of such genes offer novel targets for therapeutic intervention.
The aim of this project is to provide a better understanding of the mechanisms underlying the development of gas gangrene, an often fatal disease of particular significance to elderly and diabetic patients, who are particularly susceptible following injury, or surgery, or in some cases when suffering from colon cancer. Although research has been carried out on this disease for many years prompt surgical removal of the infected tissue, often including amputation of a limb, is still commonly used ....The aim of this project is to provide a better understanding of the mechanisms underlying the development of gas gangrene, an often fatal disease of particular significance to elderly and diabetic patients, who are particularly susceptible following injury, or surgery, or in some cases when suffering from colon cancer. Although research has been carried out on this disease for many years prompt surgical removal of the infected tissue, often including amputation of a limb, is still commonly used to ensure the patient's survival. This project involves the study of the two bacteria that are the major causes of the disease. We aim to find out how the bacteria mediate the disease, in particular to determine which toxic factors produced by the bacteria are involved. The normal host response to a bacterial infection is a rapid influx of white blood cells to the infected tissue, which is part of the normal inflammatory response. These cells engulf and degrade the bacteria, clearing the infection. However, a major characteristic of gas gangrene pathology is that very few white blood cells infiltrate the infected tissue. We aim to determine why the host fails to mount an inflammatory response to this bacterial infection. We will achieve this objective by developing a better understanding of the role of the bacterial toxins in the development of this morbid disease. It is hoped the results from this study will enable the development of more effective therapeutic and prophylactic treatments for this disease and also provide a foundation for studies into the modulation of the host response by other bacterial species.Read moreRead less