Some of the world's most important diseases, including important diseases of indigenous chilren and the hospitalised elderly are caused by bacteria that carry a surface coating called a capsule. It is not clear how this capsule is retained by bacteria. Resolution of this question could lead to the development of new disinfectants that will stop hospital-acquired infections, to new reagents that can be incoporated into medical devices where bacteria frequently grow, and new antibiotics.
Characterisation Of A Novel Type Of Promoter Controlling Expression Of Virulence Genes In Neisseria.
Funder
National Health and Medical Research Council
Funding Amount
$200,880.00
Summary
This project will investigate how two different types of bacteria control genes that are involved in determining their disease-causing ability. The expression of many bacterial genes is controlled by a sophisticated battery of regulatory systems that respond to individual, very specific, environmental signals. Such regulatory systems are capable of exerting very precise control over the level of gene expression, in response to the concentration of specific molecules in the immediate environment. ....This project will investigate how two different types of bacteria control genes that are involved in determining their disease-causing ability. The expression of many bacterial genes is controlled by a sophisticated battery of regulatory systems that respond to individual, very specific, environmental signals. Such regulatory systems are capable of exerting very precise control over the level of gene expression, in response to the concentration of specific molecules in the immediate environment. However, there is evidence to suggest that many important disease-causing bacteria are much less reliant on specific regulatory systems. Instead, these bacteria rely more heavily what have been termed global systems for the regulation of gene expression. Such systems typically respond to less specific signals, such as the growth rate of the bacterial cell, but nevertheless appear capable of very precise control. We have evidence for a previously uncharacterised type of global control system that appears to be widespread amongst bacteria. It is likely that many virulence genes in a variety of disease-causing bacteria will prove to be controlled by similar means. Therefore this project will not only provide an insight into how expression of these particular virulence determinants is regulated, but will yield data that may help in our understanding of precise global regulatory processes in other bacterial species of medical importance.Read moreRead less
Origins And Relationships Of Shigella And Enteroinvasive Escherichia Coli
Funder
National Health and Medical Research Council
Funding Amount
$377,310.00
Summary
Shigella is a well known highly infectious human pathogen with as few as 10 cells allowing effective spread by infected food or water, and also by person to person contact. Shigellosis is a particularly significant disease for children due to lack of pre-existing immunity and greater chance of transfer by fecal-oral route. One group of E. coli called Enteroinvasive E. coli (EIEC) resembles Shigella in many aspects from disease symptoms to biochemical properties. EIEC is a major cause of diarrhoe ....Shigella is a well known highly infectious human pathogen with as few as 10 cells allowing effective spread by infected food or water, and also by person to person contact. Shigellosis is a particularly significant disease for children due to lack of pre-existing immunity and greater chance of transfer by fecal-oral route. One group of E. coli called Enteroinvasive E. coli (EIEC) resembles Shigella in many aspects from disease symptoms to biochemical properties. EIEC is a major cause of diarrhoea in less developed countries and has also caused large outbreaks in developed countries. It is now clear that Shigella and E. coli are really one species. EIEC and Shigella strains are variants of E. coli with humans as the only host. However separation of the two in all records and most studies means that there is no integrated understanding of the forms. We aim to study the relationships of Shigella and EIEC and expect significant insights into the origins of Shigella-EIEC. This will facilitate diagnosis and understanding of the disease(s) and lead to a far better classification . EIEC-Shigella strains have arisen from other E. coli independently. This has happened seven times in the derivation of Shigella and we expect more such events with EIEC. An interesting phenomenon during this process is that strains tend to lose metabolic functions. In this study we will look at what, why and how functions are lost. O antigens are important in evading the host immune system. Shigella strains obtained many O antigens, the majority apparently from other species. This is quite likely the key to its success. We will look at how Shigella obtained new O antigens. This project will be significant in the understanding of Shigell-EIEC, a very significant human pathogen, and in general for understanding emergence of new pathogens.Read moreRead less
Investigation Of The Role Of Specific Mucous Associated Bacteria In Children And Young Adults With Crohns Disease
Funder
National Health and Medical Research Council
Funding Amount
$431,764.00
Summary
The role of bacteria in Crohn's disease is well accepted however to date no conclusive agents have been identified. Recent animal studies have implicated mucus-associated bacteria. We have recently shown that such bacteria, the Helicobacteriaceae, are present in humans and children with Crohn's disease. The aim of this project is to determine in children and young adults the role of these bacteria in IBD thus providing information that could be used to design improved therapies for IBD.
Investigation Of The Effects Of Polymicrobial Infection On The Induction Of Otitis Media
Funder
National Health and Medical Research Council
Funding Amount
$235,511.00
Summary
Middle ear infection is a highly prevalent paediatric disease characterised by an inflammation of the middle ear and is the most prevalent illness of childhood. It is reported that greater than 80% of children have had at least one episode of acute otitis media by 3 years of age and almost 40% of children have more than 6 episodes by age 7 years. The cause and pathogenesis of middle ear infection are multifactorial and influence of prevalence and chonicity of the infections. Prevention of bacter ....Middle ear infection is a highly prevalent paediatric disease characterised by an inflammation of the middle ear and is the most prevalent illness of childhood. It is reported that greater than 80% of children have had at least one episode of acute otitis media by 3 years of age and almost 40% of children have more than 6 episodes by age 7 years. The cause and pathogenesis of middle ear infection are multifactorial and influence of prevalence and chonicity of the infections. Prevention of bacterial middle ear infection caused by Streptococcus pneumoniae, nontypeable Haemophilus influenzae and Moraxella catarrhalis requires a much better knowledge of how these bacteria interact with each other and with the host. The poor efficacy of the current pneumococcal paediatric vaccine for preventing middle ear infections highlights this deficiency in our knowledge and will impede the development of a suitable multvalent vaccine to prevent infection by the 3 major bacterial pathogens. This study will investigate how the bacteria colonising the respiratory tract interact during infection and how they affect the host.Read moreRead less
Crohn's disease is a severe, chronic inflammatory disease of the gut which affects up to 50,000 Australians. The majority of patients develop the disease in their twenties, with significant impact on their quality of life. Our preliminary work has identified a novel gene, which could potentially cause a critical reduction in the production of anti-bacterial proteins by cells in the small bowel. Exploring the function of this gene in relation to clinical outcome could lead to better treatment.
Structural Investigations Of Bacterial Evasion Of IgA Mucosal And Systemic Immunity
Funder
National Health and Medical Research Council
Funding Amount
$488,812.00
Summary
Nose, throat and skin infections are often caused by streptococcal and staphylococcal bacteria, known as Strep Throat and Golden Staph. Infections can be life-threatening in newborns, the elderly or individuals with weak immune systems. These bacteria make proteins bind and inactivate immune proteins. Our research examines the structural basis for bacterial interactions with a key immune system protein (an antibody called IgA) and may lead to new prevention and treatment strategies.
Nucleic Acid Synthesis And Cell Division In Model Pathogenic Bacteria
Funder
National Health and Medical Research Council
Funding Amount
$781,345.00
Summary
The rise of antibiotic resistance, particularly in hospitals, over recent years represents a huge financial burden on the health system, in addition to the personal costs to the patient infected. Over the last 60 years, we have become accustomed to the availability of antibiotics that can effectively treat most, if not all, bacterial infections. Today, this is not the case, and some bacteria in hospitals are resistant to all therapeutically useful antibiotics. The costs of drug development are v ....The rise of antibiotic resistance, particularly in hospitals, over recent years represents a huge financial burden on the health system, in addition to the personal costs to the patient infected. Over the last 60 years, we have become accustomed to the availability of antibiotics that can effectively treat most, if not all, bacterial infections. Today, this is not the case, and some bacteria in hospitals are resistant to all therapeutically useful antibiotics. The costs of drug development are very considerable; from the financial perspective of a pharmaceutical company, the de novo development of new antibiotics is not attractive because they are drugs that are only used for a short period. Recoupment of development costs takes a long time. As a result, very few new antibiotics are currently in development, and many of the newer ones are the result of academic efforts and subsequent formation of spin-out companies that develop new drugs through to phase 1 trials. The need for new, and effective, antibiotic therapies is pressing. We propose to identify and validate the use of key essential biological processes as targets for the development of new antimicrobial agents in two important hospital pathogens. Staphylococcus aureus is a well known and established pathogen that is the number one cause of hospital acquired (nosocomial) infections. Acinetobacter sp. is a relatively new problem in nosocomial infections, but is growing in importance due to the startling rate at which it is able to acquire resistance to antibiotics. In both organisms, we intend to target essential protein-protein interactions involved in DNA replication (duplication of genetic material), transcription (production of a genetic message), and cell division. The targeting of protein-protein interactions, rather than the enzymic activity of a protein provides a novel and unexploited avenue for antibacterial development with great potential for success.Read moreRead less
Novel Compounds For Use As Inhibitors Of Virulence Of Human Pathogens
Funder
National Health and Medical Research Council
Funding Amount
$220,500.00
Summary
There is growing concern over the emergence of multi-drug resistant strains of bacteria which are no longer treatable with the current generation of antibiotics. This highlights the urgent need for development of the next generation of therapeutic agents to supplement or replace the current antibiotics. Our research team has identified a class of compounds which are naturally produced by a marine alga that may be effective in the control of bacterial pathogens. These compounds work by interferin ....There is growing concern over the emergence of multi-drug resistant strains of bacteria which are no longer treatable with the current generation of antibiotics. This highlights the urgent need for development of the next generation of therapeutic agents to supplement or replace the current antibiotics. Our research team has identified a class of compounds which are naturally produced by a marine alga that may be effective in the control of bacterial pathogens. These compounds work by interfering with the way many pathogens regulate the production of virulence traits. Some bacteria are able to signal members of their population by the specific uptake and recognition, through a receptor protein, of chemical cues they secrete into the environment. Accumulation of these cues or signals triggers expression of the genes that code for the virulence traits. Moreover, one particular class of these signal response proteins has been identified in many pathogens and has been shown to regulate protease production and production of a protective extracellular slime layer called a capsule. If one or more of these traits can be blocked, then the virulence of the bacterium can be reduced. We have preliminary data which demonstrates that the algal compounds do in fact prevent the expression of virulence traits and thus should be useful as new agents for the treatment of disease. The causative agents of cholera and severe gatroenteritis, Vibrio cholerae and V. parahaemolyticus respectively, have one or the other of these virulence traits, but the pathogen Vibrio vulnificus has all three and therefore is an excellent model pathogen. We propose to explore the ability of the algal compounds to specifically shut down expression of virulence factors with a long term aim for the development of these compounds as novel antimicrobial therapies for the post-antibiotic era.Read moreRead less