Defining Targets For Antifungal Stewardship In Immunocompromised Patients: Optimising Care And Safety
Funder
National Health and Medical Research Council
Funding Amount
$108,902.00
Summary
Patients with impaired immune systems are at risk of serious fungal infections. Antifungal medicines used to prevent and treat these infections can be toxic and costly. This project aims to review current antifungal use and improvement activities in place in health services, assess prescriber knowledge, and to evaluate current doses of echinocandin antifungals used in liver failure patients. This project will identify ways to improve antifungal use needed for effective and safe prescribing.
The fungal pathogen Cryptococcus neoformans is responsible for up to a million deaths annually, necessitating the development of novel antifungals. We have characterised the GTP biosynthesis enzyme IMP dehydrogenase, revealing it is critical for infection, and structural and functional analysis reveals routes to inhibitor specificity. In the proposed work will develop novel antifungal compounds that target this enzyme, as well as investigate related enzymes as potential future drug targets.
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.
Targeting Acetohydroxyacid Synthase To Discover New Antifungal Agents.
Funder
National Health and Medical Research Council
Funding Amount
$481,135.00
Summary
Invasive fungal infections are increasingly being recognized as a major life threatening risk to hospitalized patients. The efficacy of the current medications is sub-optimal due to the emergence of resistance and the high dosage regimes that are required to treat these infections. We propose to develop a new class of antifungal agent that target an enzyme, acetohydroxyacid synthase, whose activity is required for the survival of pathogenic fungi in mammals.
Targeting Fungal Phospholipid Metabolism For Antifungal Drug Discovery
Funder
National Health and Medical Research Council
Funding Amount
$828,557.00
Summary
Invasive fungal infections are a serious and escalating health problem. They cause severe disease with a high death rate and are very costly to the health system. New antifungal drugs with novel properties are needed now because there are problems with current drugs. This project aims to develop potent new antifungal drugs that are effective in many fungal diseases and are well-tolerated.
Novel Antifungal Strategies Using Drug Response Networks
Funder
National Health and Medical Research Council
Funding Amount
$484,420.00
Summary
Fungal cells are quite similar to our own making it hard to find good drug targets. This project aims to enhance current antifungal drugs with agents that interfere with iron, which is needed for fungal growth. We will see how fungal cells change the genes they use when they are treated with drugs alone and combined with molecules that mop up iron. We will then track the pathways within cells that are targets of the affected genes, and find points where these pathways can be blocked.
Improving The Therapeutic Use Of Anti-infective Agents: Application Of Pharmacometrics For Rational Dosing Regimen Design
Funder
National Health and Medical Research Council
Funding Amount
$313,390.00
Summary
There is no field of medicine in which the individualisation of medicines is more important than in infectious diseases – appropriate doses must be administered to maximise efficacy and to minimise side effects and the emergence of drug-resistance. This fellowship will use the emerging science of pharmacometrics to investigate factors contributing to the variability in response to anti-infective medications and to optimise dosing regimens for the best use of these drugs in clinical practice.
Fungal Phospholipases: A Novel Drug Discovery Platform
Funder
National Health and Medical Research Council
Funding Amount
$588,679.00
Summary
Invasive fungal infections are a serious and escalating health issue. They cause severe disease with a high death rate and are very costly to the health system. This is especially the case in immunocompromised patients, such as those with blood malignancies, organ transplant recipients and AIDS. The number of currently available drugs for the treatment of fungal infections is limited and they are, in general, either not very effective or toxic. The development of fungal strains resistant to thes ....Invasive fungal infections are a serious and escalating health issue. They cause severe disease with a high death rate and are very costly to the health system. This is especially the case in immunocompromised patients, such as those with blood malignancies, organ transplant recipients and AIDS. The number of currently available drugs for the treatment of fungal infections is limited and they are, in general, either not very effective or toxic. The development of fungal strains resistant to these drugs is also becoming problematic. There is an urgent need to discover and develop new drugs effective against fungal infections through identifying new targets in the fungal cell and-or targets that prevent the spread of infection in the human host. We were the first to describe an enzyme, phospholipase B (PLB1), which is secreted by the medically important fungus, Cryptococcus neoformans, and is important in invasion of human tissue by the fungus. It is also important in remodelling of membranes in the fungal cell. This enzyme is sufficiently different from human phospholipases to be a good target for antifungal drugs. In this project, we aim to synthesise and test molecules which should inhibit the activity of PLB and in this way block its harmful effects. We will test the effects of such drugs to make sure they do not interfere with human enzyme systems. Inhibitory compounds may also be used to kill the fungal cells, especially if administered together with currently used therapies. The design and development of new antifungal drugs with a novel mode of action represents a major advance in the treatment of fungal disease, and a saving of some A$60000 per affected patient (estimated from a recent US study).Read moreRead less