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.
Identifying And Characterising The Molecular Determinants Of Fungal Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$315,375.00
Summary
Fungi which infect humans represent one of the fastest growing public health problems. Like bacteria, fungi can pose a serious threat to infected individuals. This is especially true for individuals whose immune system is compromised in any way due to the direct action of another disease such as AIDS, treaments for diseases like cancer or treatment to prevent rejection in organ transplants. The problem is compounded by the lack of safe and effective treament for fungal infections. Many pathogeni ....Fungi which infect humans represent one of the fastest growing public health problems. Like bacteria, fungi can pose a serious threat to infected individuals. This is especially true for individuals whose immune system is compromised in any way due to the direct action of another disease such as AIDS, treaments for diseases like cancer or treatment to prevent rejection in organ transplants. The problem is compounded by the lack of safe and effective treament for fungal infections. Many pathogenic fungi are capable of growing in two very different forms. Usually only one of these forms is pathogenic and causes disease. Therefore, the genes which keep the fungus in the pathogenic form are important factors for infection. By understanding how fungi are capable of infection and avoiding the immune system, good practices and treatments can be development for these life threatening infections.Read moreRead less
Transposable Element Mobility And Chromosomal Rearrangement In The Fungal Pathogen Cryptococcus During Human Infection
Funder
National Health and Medical Research Council
Funding Amount
$322,028.00
Summary
Pathogenic fungi present in the environment have emerged as an increasingly common threat to human health. Cryptococcus neoformans and the closely related species Cryptococcus gattii are the leading causes of life-threatening fungal meningitis, and Australia is one of the few countries where both species are prevalent. Although C. neoformans is an increasingly common cause of infection in immunocompromised patients such as those suffering from AIDS, approximately one in four infected individuals ....Pathogenic fungi present in the environment have emerged as an increasingly common threat to human health. Cryptococcus neoformans and the closely related species Cryptococcus gattii are the leading causes of life-threatening fungal meningitis, and Australia is one of the few countries where both species are prevalent. Although C. neoformans is an increasingly common cause of infection in immunocompromised patients such as those suffering from AIDS, approximately one in four infected individuals has no apparent immune system defect. For patients with AIDS, in the absence of antiretroviral therapy cryptococcal infection is incurable and requires lifelong treatment with antifungal medication to keep the infection in check. During infection, Cryptococcus is under tremendous stress enforced not only by the immune system and the presence of antifungals, but also by the high temperature, nutrient limiting environment encountered in the host. The proposed research will reveal how Cryptococcus evolves in this environment to enable persistence of infection despite medical intervention. I propose that naturally occurring mobile genetic elements present in the Cryptococcus genome cause chromosomal rearrangements during long term infection to produce gene deletions and duplications that facilitate survival. By characterising these changes and the genes associated with them, the research will identify novel genes involved in pathogenesis and will increase our understanding of the infection process. The expected outcome of this project is a detailed understanding of the roles mobile element movement and chromosomal rearrangement play in Cryptococcus during infection, and how these affect genes that contribute to the pathogenic process. The fundamental knowledge gained from this study will facilitate studies designed to combat infections in the clinical setting, provide new drug targets and help foster the development of more effective therapies.Read moreRead less
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.
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
The Role Of Fatty Acid Metabolism In Pathogenicity.
Funder
National Health and Medical Research Council
Funding Amount
$540,075.00
Summary
Fungi which infect humans are a major health problem, especially for those with compromised immune systems (eg. AIDS, transplant and cancer patients). Pathogenic fungi must evade the host s immune system whilst deriving nutrients for growth. Some fungi evade the immune system by residing within host cells. This poses significant challenges to growth due to the nutrient poor environment. By understanding how these fungi adapt to growth inside host cells, new avenues for treatment will emerge.
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.
Evolutionary Events Shaping The Genome Of Cryptococcus Neoformans And Their Effects On Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$387,489.00
Summary
Recurring infection in patients with fungal meningitis caused by Cryptococcus neoformans is typically caused by persistence of the original infection rather than reinfection with a new strain. Our analysis of relapse strains shows that small-scale alterations frequently occur at the chromosome ends - regions containing important pathogenesis-related genes in other pathogens. We seek to characterise this microevolution further to understand how it contributes to the success of this pathogen.