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.
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.
Characterizing The Molecular Mechanisms Of Clinically Important Bacterial-fungal Interactions; The Potential To Uncover Novel Therapeutic Targets
Funder
National Health and Medical Research Council
Funding Amount
$480,492.00
Summary
In hospitals and in nature, diverse microbes, such as bacteria and fungi, often live in close proximity to each other. Their interactions can either be helpful or detrimental to one another, and such interactions are likely important for their ability to cause human disease. This proposal aims to study the mechanisms by which bacteria interact with fungi and by doing so, will identify important mechanisms of how microbes cause human illness and also uncover new targets for antibiotic development ....In hospitals and in nature, diverse microbes, such as bacteria and fungi, often live in close proximity to each other. Their interactions can either be helpful or detrimental to one another, and such interactions are likely important for their ability to cause human disease. This proposal aims to study the mechanisms by which bacteria interact with fungi and by doing so, will identify important mechanisms of how microbes cause human illness and also uncover new targets for antibiotic development.Read moreRead less
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.
An Investigation Into Mitochondrial Dynamics In The Human Pathogen Candida Albicans
Funder
National Health and Medical Research Council
Funding Amount
$581,966.00
Summary
Our goal is to find new therapies to treat infections with Candida albicans, a major human pathogen that causes highly fatal hospital-associated disease. We have identified the mitochondrion, the cellular powerhouse, as a promising target for the development of new anti-candida drugs. We will use innovative imaging and molecular approaches, together with experimental animal infection models to understand how mitochondria could be inhibited to treat life-threatening infections with Candida.
An Investigation Into Pathogen-specific Factors Required For Drug-resistance And Viability Of Candida Albicans
Funder
National Health and Medical Research Council
Funding Amount
$337,614.00
Summary
We identified proteins required for growth and drug resistance of the fungus Candida albicans, a major hospital-acquired human pathogen. Candida infections target the immunocompromised and mortality is huge (?30-50%). We will use cell biology, genetics and biochemistry to characterise these proteins. Importantly, these factors are present in fungi, but absent from humans. Therefore our study will help development of new strategies for antifungal treatments.
Cryptococcal Meningoencephalitis - Fungal Determinants Of Invasion Of The CNS
Funder
National Health and Medical Research Council
Funding Amount
$587,634.00
Summary
Meningitis and brain infection (meningoencephalitis) due to the fungus Cryptococcus, affect over 1 million patients with AIDS annually, especially in developing countries; with more than 600,000 deaths. It is not known how Cryptococci cross from the blood stream into the brain; this must be elucidated in order to prevent and/or control this devastating infection. This project will determine how cryptococci influence host blood cells to act as “Trojan horses” and/or release products that initiate ....Meningitis and brain infection (meningoencephalitis) due to the fungus Cryptococcus, affect over 1 million patients with AIDS annually, especially in developing countries; with more than 600,000 deaths. It is not known how Cryptococci cross from the blood stream into the brain; this must be elucidated in order to prevent and/or control this devastating infection. This project will determine how cryptococci influence host blood cells to act as “Trojan horses” and/or release products that initiate invasion of brain tissue and meningitis.Read moreRead less
Pathogenesis Of A New Mouse Model Of Ankylosing Spondylitis
Funder
National Health and Medical Research Council
Funding Amount
$682,820.00
Summary
Ankylosing spondylitis and Crohn's disease are autoimmune inflammatory diseases which cause long-term pain and deformity of joints, spine and bowel. Using a new mouse model of both diseases, we will study cells and processes involved in the initiation of disease, in order to discover new targets for prevention and treatment. The work will have importance for design of new therapies for human inflammatory spine and bowel diseases.
Signalling Pathways And Fungal Virulence – The Inositol Polyphosphate Kinase Pathway In Cryptococcus Neoformans
Funder
National Health and Medical Research Council
Funding Amount
$545,189.00
Summary
Bloodstream fungal infections kill millions of people per year world-wide and are costly to treat. A potentially fruitful strategy for developing new, urgently-needed drugs to fight these infections, is to target signalling pathways, which in fungi, are essential for establishing infection. This proposal investigates how one such pathway, the inositolpolyphosphate kinase pathway, allows fungi to establish infection and will determine which components are suitable targets for drug development.
Dissecting Virulence Attributes In A Human Pathogenic Fungus
Funder
National Health and Medical Research Council
Funding Amount
$814,596.00
Summary
Fungi that infect humans are a major health problem worldwide, particularly for those with compromised immune systems (eg. AIDS, transplant and cancer patients). These fungi cause disease by evading the immune system whilst deriving nutrients for growth. Some fungi evade the immune system by residing within host cells; a hostile and nutrient poor environment. This project will study genes that are required for growth inside host cells. This knowledge will open new avenues for treatment.