The pathogen Cryptococcus neoformans is responsible for hundreds of thousands of deaths annually. If the infection is survived, relapse caused by evolved forms of the original infecting strain is common. Our research has uncovered similar genetic changes in isolates from unrelated patients that implicate epigenetic processes in relapse and reveal potential vulnerabilities of the pathogen. The proposed work is to investigate these changes to assist in our antifungal drug development efforts.
Is The Excess Mortality Amongst Tuberculosis Survivors Explained By Chronic Pulmonary Aspergillosis? Investigating Burden, Diagnosis, And Therapy
Funder
National Health and Medical Research Council
Funding Amount
$645,205.00
Summary
Chronic pulmonary aspergillosis (CPA) is a serious lung infection due to the mould Aspergillus. It affects people with damaged lungs, such as those who have had tuberculosis. In Vietnam, TB is extremely common, and there should be many cases of CPA. However, because diagnostic facilities are poor, CPA is often wrongly labelled as failed TB treatment, and patients receive the wrong therapy. My research will determine the size of the problem in Vietnam and how best to address it.
Immuno-metabolic Interactions Of The Fungal Superbug Candida Auris
Funder
National Health and Medical Research Council
Funding Amount
$674,105.00
Summary
Infections threaten hospital patients and undermine our ability to use advanced medical treatments for conditions such as cancer. Candida auris is an emerging superbug causing infections in hospitals and nursing homes that are commonly resistant to front-line antifungal therapy. To build the knowledge foundation for improved treatments, this proposal aims to define how C. auris escapes immune defences and understand the metabolic mechanisms that shape immune responses and infection outcomes.
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.
Fungal Determinants And Host Cell Death Signals In Fatal Candida Infections
Funder
National Health and Medical Research Council
Funding Amount
$654,091.00
Summary
Fungal pathogens are a major burden in hospital settings as they evade the immune system and cause lethal sepsis. This project will determine the molecular factors utilized by the fungal pathogen Candida to kill host immune cells. We will investigate whether immune cell death contributes to the high fatality rate, commonly associated with systemic Candida infections, and whether this can be targeted by novel therapeutics.
Cellular And Molecular Mechanisms Of Fungal Infection Pathogenesis And Therapy
Funder
National Health and Medical Research Council
Funding Amount
$561,028.00
Summary
Fungal infections are serious problems for patients with depressed immunity such as chemotherapy or transplant patients. More effective antifungal treatments are needed. We will study a model of fungal infection in zebrafish embryos that recapitulates human penicilliosis. The research will study how the infection establishes and how different types of white blood cells either help or hinder infection establishment. The results will point to new approaches for treating serious fungal infections.
Finding Therapeutic Targets For An Opportunistic Human Fungal Pathogen
Funder
National Health and Medical Research Council
Funding Amount
$404,068.00
Summary
Penicillium marneffei is a fungus that causes disease in patients with depressed immunity. This project models this infection in zebrafish, which have advantages for modelling infectious disease. It uses fluorescent fungi and fish with fluorescent immune cells to study the way white blood cells fight this infection, and mutant zebrafish and mutant fungi to find new therapeutic targets in the host-pathogen interaction.
Predicting The Risk Of Invasive Candidiasis In Critically Ill Patients
Funder
National Health and Medical Research Council
Funding Amount
$1,258,287.00
Summary
Invasive fungal infections (such as bloodstream infections) are a serious and increasing problem for critically ill patients managed in the Intensive Care Unit. Outcomes can be improved by giving early treatment only to those at highest risk of fungal infection. Our aim is to easily identify those at high-risk. Patients treated in seven major ICUs will be observed and a simple and accurate method of scoring their illness characteristics and amount-types of fungi present will be developed.
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