Improving Subunit Vaccines Against Tuberculosis For Pulmonary Delivery
Funder
National Health and Medical Research Council
Funding Amount
$635,320.00
Summary
Tuberculosis is an enormous health problem globally and remains a threat to Australia because of our proximity to high burden countries. The development of better vaccines against TB is crucial to reducing disease and preventing transmission. We shall develop and test new TB vaccines composed of a protective TB protein and immune-stimulating molecules in dry powder which can be safely delivered to the lungs. This respirable vaccine will be used to protect against TB and boost the effects of BCG.
Multistage Vaccines For The Prevention Of Tuberculosis
Funder
National Health and Medical Research Council
Funding Amount
$884,290.00
Summary
Almost two million people die from tuberculosis (TB) each year. The current vaccine, BCG, is ineffective at controlling TB and the type of immune response needed to protect against the disease is poorly understood. We have discovered new antigens of the TB bacterium, and we will combine them with novel delivery strategies to develop new TB vaccines. We will also determine the type of immune response needed to protect against TB, which will aid progression of vaccines into clinical trials.
A New Class Of Inhibitors For The Treatment Of Tuberculosis
Funder
National Health and Medical Research Council
Funding Amount
$720,691.00
Summary
Tuberculosis (TB) remains a major cause of mortality and morbidity worldwide, with 1.3 million deaths annually. Some strains of the TB bacterium are resistant to all available drugs. We have identified novel chemical structures that display potent and specific activity against pathogenic mycobacteria. In this proposal we will develop optimised derivatives with more potent activity against mycobacteria, assess their stability and toxicity and determine their mode of action.
An Ace Up Their Sleeve: Characterisation Of A Novel Family Of Drug Efflux Systems Represented By The Acinetobacter AceI Exporter
Funder
National Health and Medical Research Council
Funding Amount
$400,286.00
Summary
Chlorhexidine is widely used as an antiseptic in products such as skin washes, soaps, mouthwashes, disinfectants and preservatives. We have recently discovered a novel bacterial protein which pumps chlorhexidine out of bacterial cells to make them resistant to this antiseptic agent. This proposal aims to understand this resistance mechanism and to find inhibitors which could be applied in clinical settings to augment the activity of chlorhexidine.
Reversing Antibiotic Resistance With Efflux Pump Inhibitors
Funder
National Health and Medical Research Council
Funding Amount
$494,174.00
Summary
Antibiotic resistance in dangerous pathogens is one of the greatest threats to human health of the 21st century. The main cause of multidrug resistance is the presence of drug efflux pumps, which remove antibiotics from the bacterial cell thereby lowering the antibiotic concentration inside the cells to sub-toxic levels. We will use our expertise on these efflux pumps and on how to inhibit them to develop compounds that could reverse resistance and restore the activity of antibiotics.
Beta-lactamase Mediated Antibiotic Resistance In Gram-negative Pathogens: How Does Genotype Relate To Phenotype?
Funder
National Health and Medical Research Council
Funding Amount
$397,869.00
Summary
Unfortunately, one of the consequences of antibiotic usage (and in particular over-use and mis-use) is the development of resistance; if a small proportion of bacteria survive treatment, they can grow and replace the previous population of sensitive bacteria. In addition, the genes that confer resistance can be transferred between different bacterial lineages, thus facilitating the dissemination of resistant bacteria. The most important mechanism of penicillin resistance is through the expressio ....Unfortunately, one of the consequences of antibiotic usage (and in particular over-use and mis-use) is the development of resistance; if a small proportion of bacteria survive treatment, they can grow and replace the previous population of sensitive bacteria. In addition, the genes that confer resistance can be transferred between different bacterial lineages, thus facilitating the dissemination of resistant bacteria. The most important mechanism of penicillin resistance is through the expression of an enzyme called a beta-lactamase. This enzyme breaks down the penicillin. Beta-lactamase enzymes come in many different varieties, and new varieties appear quite frequently. Remarkably, when new kinds of penicillin are invented to circumvent resistance, the appearance of new beta-lactamases that can break down these new penicillins follows shortly thereafter. The objectives of our research are twofold. Firstly, it is now clear that the relationship between the beta-lactamase genes in a bacterium and the resulting pattern of resistance can be very complex. It can involve both the broad nature of the genes, the numbers of duplicates of the genes inside the cell, and very minor changes to the gene sequences. We will probe the relationship between the gene and resistance so as to understand it at a deeper level. Secondly, we will use this information to develop very efficient and cost affective methods for keeping track of the spread of the different varieties of beta-lactamase genes. These methods will be designed to be carried out on real-time PCR machines. These high-tech devices are general purpose gene analyzers that can carry out many different kinds of genetic assay. They are rapidly becoming ubiquitous in clinical microbiology laboratories. The use of these methods will provide much hard information that will be used to minimise the dissemination of antibiotic resistance.Read moreRead less
Design, Development And Analysis Of New Tuberculosis Drugs
Funder
National Health and Medical Research Council
Funding Amount
$736,628.00
Summary
Serious issues of drug resistance have emerged in tuberculosis prevention and are placing enormous pressure on global health systems. We have identified an enzyme of M. tuberculosis that is essential for its survival. This project will develop potent inhibitory compounds for this enzyme. Further, we will identify new drug targets through a screen to specifically identify the genes of the organism essential for its survival in the body. This information will be used to develop new TB drugs.
Exploitation Of Bacterial Transcription Initiation As A Target For New Antimicrobials
Funder
National Health and Medical Research Council
Funding Amount
$540,356.00
Summary
Antibiotic resistant infections from 'superbugs' are a major health problem. We will exploit information we have gathered on the machinery that copies genetic information into a message to discover chemical compounds that can be used for the development of new antibiotics with a novel mechanism of action.
Determining The Bacterial Contributions To Tuberculosis And Identification Of Drug Targets
Funder
National Health and Medical Research Council
Funding Amount
$443,946.00
Summary
Serious issues of drug resistance have emerged in tuberculosis prevention and are placing enormous pressure on global health systems. We have identified an enzyme of M. tuberculosis that is essential for its survival. This project will develop potent inhibitory compounds for this enzyme. Further, we will identify new drug targets through a screen to specifically identify the genes of the organism essential for its survival in the body. This information will be used to develop new TB drugs.
Manipulating Immunity To Mycobacterium Tuberculosis With Novel Vaccines And Immunotherapeutics
Funder
National Health and Medical Research Council
Funding Amount
$524,770.00
Summary
Tuberculosis (TB) is an enormous world health problem with 2 million deaths per year and an estimated one third of the world s population infected with the TB bacterium. People who become infected with the bacterium and cannot clear the infection are at great risk of developing TB later in life. Control of TB is confronted with two major problems. First, the only vaccine available for TB, known as BCG, is not very effective at preventing the disease. We do not know why BCG is not an effective va ....Tuberculosis (TB) is an enormous world health problem with 2 million deaths per year and an estimated one third of the world s population infected with the TB bacterium. People who become infected with the bacterium and cannot clear the infection are at great risk of developing TB later in life. Control of TB is confronted with two major problems. First, the only vaccine available for TB, known as BCG, is not very effective at preventing the disease. We do not know why BCG is not an effective vaccine and the type of immune response required to achieve optimal protection against TB is not fully understood. Second, the drugs currently used to treat TB are expensive, treatment times are long and drug resistance is increasing at an alarming rate. Therefore there is an urgent need to develop new vaccines and therapies against TB. We propose to use animal models of TB infection and sophisticated immunological techniques to compare immune responses generated by TB, BCG and new generation vaccines developed in our laboratory. This will allow us to identify the key features of a vaccine that results in effective, long-lasting protection against TB infection. Novel strategies to increase the immune response in the lung, the main site of TB infection, will also be examined. This will involve pulmonary delivery of molecules that increase the number and effectiveness of lung antigen presenting cells, which are necessary to drive the right type of immune response to eradicate the TB bacterium. Increasing lung immunity will be used to either boost the effect of the BCG vaccine, or as a therapy to kill the bacterium in those already infected. This is an internationally competitive project and our team is at the forefront of this research effort. The development of new vaccines to prevent TB or new strategies to treat established TB infection would be a major medical breakthrough and a represent a significant achievement for Australian health and medical research.Read moreRead less