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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
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
The Molecular Basis Of Bacterial Infectious Diseases
Funder
National Health and Medical Research Council
Funding Amount
$16,230,996.00
Summary
Bacterial infectious diseases are a serious threat to human health, accounting for over 10 million deaths each year. This multidisciplinary collaborative team is investigating the complex interactions between major disease-causing bacteria and their human hosts, in order to determine how they cause disease. These studies will make a major contribution to fundamental knowledge in this field. This information is also essential for the development of cheaper and more effective vaccines, as well as ....Bacterial infectious diseases are a serious threat to human health, accounting for over 10 million deaths each year. This multidisciplinary collaborative team is investigating the complex interactions between major disease-causing bacteria and their human hosts, in order to determine how they cause disease. These studies will make a major contribution to fundamental knowledge in this field. This information is also essential for the development of cheaper and more effective vaccines, as well as novel drugs. These are urgently needed to reduce death and illness due to bacterial infectious diseases in the 21st century. 11Read moreRead less
This program will investigate the strategies used by pathogenic bacteria to cause human diseases. The research will focus on how bacteria initiate infections, how they invade, cause cell and tissue damage and respond to their human host. It will also examine how the host’s innate immune system interacts with these bacteria. The results will provide new insights into host-pathogen interactions and reveal new targets for the development of novel antibacterial drugs and vaccines.
Transposable Element Mobility And Chromosomal Rearrangement In The Fungal Pathogen Cryptococcus During Human Infection
Funder
National Health and Medical Research Council
Funding Amount
$322,028.00
Summary
Pathogenic fungi present in the environment have emerged as an increasingly common threat to human health. Cryptococcus neoformans and the closely related species Cryptococcus gattii are the leading causes of life-threatening fungal meningitis, and Australia is one of the few countries where both species are prevalent. Although C. neoformans is an increasingly common cause of infection in immunocompromised patients such as those suffering from AIDS, approximately one in four infected individuals ....Pathogenic fungi present in the environment have emerged as an increasingly common threat to human health. Cryptococcus neoformans and the closely related species Cryptococcus gattii are the leading causes of life-threatening fungal meningitis, and Australia is one of the few countries where both species are prevalent. Although C. neoformans is an increasingly common cause of infection in immunocompromised patients such as those suffering from AIDS, approximately one in four infected individuals has no apparent immune system defect. For patients with AIDS, in the absence of antiretroviral therapy cryptococcal infection is incurable and requires lifelong treatment with antifungal medication to keep the infection in check. During infection, Cryptococcus is under tremendous stress enforced not only by the immune system and the presence of antifungals, but also by the high temperature, nutrient limiting environment encountered in the host. The proposed research will reveal how Cryptococcus evolves in this environment to enable persistence of infection despite medical intervention. I propose that naturally occurring mobile genetic elements present in the Cryptococcus genome cause chromosomal rearrangements during long term infection to produce gene deletions and duplications that facilitate survival. By characterising these changes and the genes associated with them, the research will identify novel genes involved in pathogenesis and will increase our understanding of the infection process. The expected outcome of this project is a detailed understanding of the roles mobile element movement and chromosomal rearrangement play in Cryptococcus during infection, and how these affect genes that contribute to the pathogenic process. The fundamental knowledge gained from this study will facilitate studies designed to combat infections in the clinical setting, provide new drug targets and help foster the development of more effective therapies.Read moreRead less
Identification Of Proteins Specific To Transmissible Pseudomonas Aeruginosa In Cystic Fibrosis Infection
Funder
National Health and Medical Research Council
Funding Amount
$443,007.00
Summary
Cystic fibrosis (CF) is the most common autosomal recessive disorder in humans, affecting 1:2000 people. Mortality is often caused by Pseudomonas aeruginosa lung infections which have recently been shown to occur not only environmentally but also via person-person contact, usually during CF clinic visits. This project will elucidate the molecular traits responsible for these 'epidemic' P. aeruginosa infections, with the aim of finding novel therapeutics and infection control strategies.
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
Functional Genomic Analysis Of Exported DNA J Molecules In The Malaria Parasite Plasmodium Falciparum
Funder
National Health and Medical Research Council
Funding Amount
$529,698.00
Summary
Every day 3500 people die of malaria and more than 40% of the world s population is at risk. Malaria is one of the biggest scourges of mankind. This project aims to translate the available genomic data into functional insights using frontier technology to identify new intervention targets for P. falciparum infection. Developing novel targets against malaria is important from a humanitarian point of view, and also to safeguard Australia and its neighbouring regions against the social and economic ....Every day 3500 people die of malaria and more than 40% of the world s population is at risk. Malaria is one of the biggest scourges of mankind. This project aims to translate the available genomic data into functional insights using frontier technology to identify new intervention targets for P. falciparum infection. Developing novel targets against malaria is important from a humanitarian point of view, and also to safeguard Australia and its neighbouring regions against the social and economical implication of this disease. The malaria parasite seeks shelter from the host immune system by hiding in red blood cells, but at the same time it has to stay in contact with the blood environment. This is achieved by export of virulence factors onto the surface of malaria parasite-infected red blood cells, which are essential for the maintenance of malaria infection. Without these virulence factors the body's immune system can get rid of the malaria parasites by itself. For display on the surface the proteins have to pass several membranes and are transferred through the red blood cell. The whole transport and assembly process of the virulence factors into functional units is very complex and requires several helper and co-helper molecules. With the deciphering of the malarial genetic code it became obvious that the parasite displays an unusual large number of co-helper molecules, which are putatively exported into the red blood cell. We will generate transgenic parasites deficient in the expression of these exported co-helper proteins and assess their role on the pathogenesis of this debilitating infectious disease.Read moreRead less
Elucidation Of Proteins Expressed By Pathogenic Fungi During Animal Infection
Funder
National Health and Medical Research Council
Funding Amount
$558,267.00
Summary
Fungi cause a diverse range of diseases and are very difficult to treat. This project looks at the proteins that are made by infectious fungi while they are causing disease in animal cells. Proteins made in particularly high abundance may be essential for the fungus to live and grow in animal tissues. By specifically targeting their production, it should be possible to stop the infection without harming the host cell.
Identifying The Physiological Conditions That Promote Lateral Gene Transfer And Evolution Of New Streptococcal Pathovars
Funder
National Health and Medical Research Council
Funding Amount
$415,907.00
Summary
In the last few decades, the diseases caused by the three human pathogens, groups A, B and G streptococcus have undergone a transformation. The exchange of DNA between these species is speculated to play a role in this changing disease association. In this proposal we will identify the specific physiological and growth conditions that promote DNA transfer. Such information may help in our understanding of how new pathogenic strains of streptococci arise.