Novel Therapeutic Strategy Against Multidrug-resistant Gram-negative Bacteria
Funder
National Health and Medical Research Council
Funding Amount
$349,823.00
Summary
In the past two decades, there has been a marked decline in discovery and development of new antibiotics while there has been a remarkable increase in resistance to the currently available antibiotics. The growth in the number of resistant bacteria and lack of antibiotics available for treatment is very significant with gram-negative bacteria, such as Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia. Colistin, an old antibiotic that has been used little over the l ....In the past two decades, there has been a marked decline in discovery and development of new antibiotics while there has been a remarkable increase in resistance to the currently available antibiotics. The growth in the number of resistant bacteria and lack of antibiotics available for treatment is very significant with gram-negative bacteria, such as Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia. Colistin, an old antibiotic that has been used little over the last 40-50 years, has been 'taken off the shelf' and is now being used as a last line of defence to treat people with infections caused by these bacteria. Clearly, doctors and their infected patients will be in an even more precarious position than currently exists if resistance to colistin increases. We have discovered a novel therapeutic strategy that is able to reverse colistin resistance in P. aeruginosa. The studies proposed in this project will investigate this novel strategy across a range of multidrug-resistant bacteria and provide the information essential for rational use in patients. We propose that such a novel therapeutic strategy will provide a powerful weapon for the war on these 'superbugs'.Read moreRead less
Characterisation Of A Type V Secretion In Escherichia Coli And Determining Its Role In Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$73,195.00
Summary
Disease causing bacteria assemble secretion systems to assist with colonisation, persistence and destruction of host tissue. These systems have been categorised as Type I to Type VI. A comprehensive understanding of these secretion systems, is of paramount importance for a complete understanding of bacterial pathogenesis. We will investigate the role of a novel Type V secretion system conserved amongst many human pathogens.
Antibiotic Resistance And Multiple Antibiotic Resistance In Human Commensal Escherichia Coli In Australia
Funder
National Health and Medical Research Council
Funding Amount
$509,202.00
Summary
Antibiotic resistance, particularly resistance to all or nearly all of the antibiotics available for treatment is now very common and impacts heavily on the treatment of bacterial infections. This project will track resistance genes in reservoirs where antibiotic resistance genes may be present in high concentrations as these are a likely source of the resistance genes in disease-causing bacteria. One such reservoir, the bacteria in the intestines of healthy humans will be examined.
Molecular Characterization Of The Gingipains Of Porphyromonas Gingivalis
Funder
National Health and Medical Research Council
Funding Amount
$394,000.00
Summary
Chronic periodontitis is a bacteria-associated inflammatory disease of the supporting tissues of the teeth, which results in the destruction of tooth support and ultimately leads to tooth loss. The disease is a major public health problem with a large economic burden and has been associated with an increased risk of cardiovascular disease and pre-term birth and low birth weight. The bacterium Porphyromonas gingivalis has now been identified as a major pathogen in the development of chronic perio ....Chronic periodontitis is a bacteria-associated inflammatory disease of the supporting tissues of the teeth, which results in the destruction of tooth support and ultimately leads to tooth loss. The disease is a major public health problem with a large economic burden and has been associated with an increased risk of cardiovascular disease and pre-term birth and low birth weight. The bacterium Porphyromonas gingivalis has now been identified as a major pathogen in the development of chronic periodontitis. We have identified a major virulence factor of P. gingivalis which is an extracellular complex of proteins involved in binding and destroying host proteins. The aim of this proposal is to characterize the secretion, molecular processing and assembly of the cell surface complex using state-of-the-art proteomic techniques. This study will provide valuable insight into the molecular processes of a bacterial pathogen that leads to virulence. Detailed knowledge on the unique molecular events involved in secretion, processing and assembly of a major virulence factor will provide molecular targets for the development of specific inhibitors that may have utility as an adjunctive therapeutic and-or as part of a preventive regime or maintenance program for the control of chronic periodontitis. Further, the molecular insight that will result from this study will have broader application in the understanding of virulence factor processing of a Gram-negative pathogen that will provide paradigms for other bacterial pathogens.Read moreRead less
Targeting Polymyxin-resistant Gram-negative Superbugs: Development Of Novel Antimicrobial Lipopeptides
Funder
National Health and Medical Research Council
Funding Amount
$661,069.00
Summary
Prevalence of resistance to antibiotics among Gram-negative 'superbugs' is a major global medical challenge, which is highlighted by the Bad Bugs, No Drugs campaign of the Infectious Diseases Society of America. There are virtually no new antibiotics in the current drug development pipeline for these dangerous pathogens. In this project, novel lipopeptides will be designed, synthesised and evaluated against these 'superbugs'. Information obtained will be crucial for further drug development.
Towards An Understanding Of Dynamic Genetic Regulation At A Global Scale In Bacteria: A Systems Biology Approach
Funder
National Health and Medical Research Council
Funding Amount
$486,000.00
Summary
To achieve major breakthroughs in the understanding of the regulation of gene transcription in bacteria at a global scale. High throughput technologies (living cell arrays, tiling DNA microarrays, multidimensional liquid chromatography proteomics and quantitative metabolomics) will be developed in conjunction with new computational modelling concepts to facilitate the understanding of biological complexity. The iterative process of simulations and model driven targeted experiments will generate ....To achieve major breakthroughs in the understanding of the regulation of gene transcription in bacteria at a global scale. High throughput technologies (living cell arrays, tiling DNA microarrays, multidimensional liquid chromatography proteomics and quantitative metabolomics) will be developed in conjunction with new computational modelling concepts to facilitate the understanding of biological complexity. The iterative process of simulations and model driven targeted experiments will generate novel hypotheses about the mechanistic nature of dynamic cellular responses, unravel emerging systems properties, and ultimately provide an efficient roadmap to tackle novel, pathogenic organisms.The role of my laboratory in this project is to perform subcellular localisation of transcription factors, establish standard operating procedures (with other groups) for growth, imaging and image analysis, precisely quantify 6 transcription factors under 3 standardised growth conditions for incorporation into metabolic models, and perform some analysis of transcription complexes.Read moreRead less
The Role Of Interferon-regulatory Factors In The Host Defense Against Bacterial Infection
Funder
National Health and Medical Research Council
Funding Amount
$355,711.00
Summary
Type I interferons are used in the treatment of viral infection. However, the therapeutic potential of type I interferons for the treatment of bacterial infection is not known because we do not fully understand their functional roles and regulation in hosts infected with bacteria. My proposal aims to investigate the role of one family of regulatory proteins, known as interferon-regulatory factors, in the host defense against foodborne bacteria.
Negative Symptom Formation In Schizophrenia: An Electrophysiological, Neurophysiological And Computational Modelling Investigation
Funder
National Health and Medical Research Council
Funding Amount
$374,508.00
Summary
The Negative and cognitive symptoms of schizophrenia have been recognised as being just as disabling as the more widely recognised positive symptoms such as hallucinations and delusions. Recently it has been proposed that negative symptoms in schizophrenia might be caused by alterations in learning from rewards and punishments. This project will investigate brain activity in people with schizophrenia during reward and punishment based learning tasks while applying computational modelling.
CD4+ T Cell-independent Immunity Against Salmonellae
Funder
National Health and Medical Research Council
Funding Amount
$550,226.00
Summary
Salmonella typhimurium is an important pathogen in both developed and developing countries where it causes significant HIV-linked morbidity. There is a pressing need to understand how immunity might be established against this organism that will function when the patient is immunocompromised either through age or through a comorbidity like HIV.