Processes Underlying Establishment And Maintenance Of The Latent HIV Resevoir And Potential Impact Of Integrase Inhibitors
Funder
National Health and Medical Research Council
Funding Amount
$318,044.00
Summary
Therapy for HIV-infected individuals is currently able to control the growth of the virus, but cannot eradicate the viral infection. This is due to a pool of CD4+ T lymphocytes which contain HIV DNA in a latent state, ready to reactivate as soon as therapy is interrupted. This project aims to better understand how this pool of latently infected CD4+ T lymphocytes is established and maintained, particularly how it is linked to the essential T cell survival signal from interleukin 7.
RECOMBINANT MALARIAL PYRIMIDINE ENZYMES AS DRUG TARGETS
Funder
National Health and Medical Research Council
Funding Amount
$229,750.00
Summary
Malarial parasites have now developed resistance to most of the available drugs and there is an urgent need for drugs with new mechanisms of action. Institutions collaborating on the Malarial Genome Project have sequenced the majority of DNA in the 14 chromosomes. The nucleotide sequence available on the internet contains thousands of open reading frames (ORFs) which encode proteins essential for survival of the parasite. Many of these proteins are enzymes which are suitable targets for drug dev ....Malarial parasites have now developed resistance to most of the available drugs and there is an urgent need for drugs with new mechanisms of action. Institutions collaborating on the Malarial Genome Project have sequenced the majority of DNA in the 14 chromosomes. The nucleotide sequence available on the internet contains thousands of open reading frames (ORFs) which encode proteins essential for survival of the parasite. Many of these proteins are enzymes which are suitable targets for drug development. A knowledge of the molecular architecture of the active site of such enzymes provides a template for drug design. The malarial parasite, Plasmodium falciparum, can only synthesise pyrimidine nucleotides for DNA via the de novo pyrimidine pathway. We have cloned the genes encoding three of the enzymes of the de novo pathway using sequence information from the Malarial Genome Project. Dihydroorotase, orotate phosphoribosyltransferase, and OMP decarboxylase, catalyse reactions 3, 5 and 6 of the pathway. We have expressed these enzymes in the bacterium Escherichia coli enabling large-scale production of these drug targets. We propose to characterise the catalytic and inhibitory properties of these enzymes, and grow protein crystals for determination of atomic structures by x-ray diffraction. The structures will provide templates for rational design of new antimalarial drugs. In a second approach for develoment of new drugs, the 3 malarial enzymes will be screened against chemical libraries for inhibition of catalytic activity. The initial screen will utilise a high throughput Biacore 3000 instrument which detects strong interactions between a target enzyme and candidate inhibitors. A thorough knowledge of the catalytic mechanisms, the three-dimensional structures and novel first generation inhibitors of these 3 malarial target enzymes, will provide a strong basis for development of new antimalarial drugs.Read moreRead less
Novel Artemisinin-based Combination Therapies For Children Exposed To High Transmission Of Multiple Plasmodium Species
Funder
National Health and Medical Research Council
Funding Amount
$1,378,408.00
Summary
We recently found that the WHO-recommended combination antimalarial therapy artemether-lumefantrine and the candidate regimen dihydroartemisinin-piperaquine were not fully effective for both falciparum and vivax malaria in young PNG children, a group at risk of complications and death. We plan to study two new combinations (artesunate-pyronaridine and artemisinin-naphthoquine) and hypothesise that at least one will prove superior and be used as first-line treatment in PNG and similar countries.
Centre Of Research Excellence In Indigenous Children's Healthy EARs (ICHEAR)
Funder
National Health and Medical Research Council
Funding Amount
$2,615,897.00
Summary
The overwhelming burden of otitis media (middle ear inflammation, OM) and the consequences of hearing loss on social and educational outcomes in Indigenous children are indisputable. Our CRE_ICHEAR is a multidisciplinary group of Australia’s experts in OM research, policy and practice guidelines. The CRE will derive better value in terms of discovery, translation and sustainability. Increased Indigenous leadership will raise awareness and advocacy, with greater efficiency of research translation
Enhancing Clinical Management Of Paediatric Malaria In Endemic Areas With Transmission Of Multiple Plasmodium Species
Funder
National Health and Medical Research Council
Funding Amount
$867,511.00
Summary
Malaria remains a major problem for children in developing countries especially where different types of the disease are common. This set of complementary studies, based at an established research site in PNG aims to develop new treatment strategies for childhood malaria. A novel method of giving medicine via a spray under the tongue for sick children before arrival at hospital and modified dosing schedules of an old drug used for treating parasites hidden in the liver will be studied.
Risk Factors, Mechanisms, And Treatment Of Knowlesi Malaria
Funder
National Health and Medical Research Council
Funding Amount
$265,138.00
Summary
The monkey parasite P. knowlesi is an increasing cause of human malaria in SE Asia. My studies on the clinical epidemiology, diagnosis and treatment of non-severe and severe malaria in Malaysia have changed policy. I will further define the clinical epidemiology of malaria patients in this area over time, assess risk factors for knowlesi malaria, and evaluate the role of human and parasite factors in disease severity, and treatment for reducing acute kidney injury in knowlesi malaria.
Intensive Care patients more often than not, develop kidney failure requiring dialysis. Unfortunately there is little information available to inform clinicians of appropriate doses for antibiotics in these patients, putting them at an increased risk of death from ineffective treatment. Our project aims to develop dosing guidelines for the many types of dialysis used globally to achieve concentrations in the blood that optimise antibiotic effects in these most critically ill patients.
Primaquine Radical Cure Of Plasmodium Vivax Malaria: A Risk-benefit Analysis
Funder
National Health and Medical Research Council
Funding Amount
$122,714.00
Summary
Vivax malaria causes significant morbidity with over 100 million clinical cases each year and can cause a relapsing illness and chronic anaemia. The only available radical cure of P. vivax requires administration of primaquine, which can cause severe haemolysis in some patients. Our research aims to determine the risks and benefits of giving primaquine to cure vivax malaria using data from meta-analyses of published clinical trials and individual patient results from large multicentre trials.
The Epidemiology And Treatment Of Infections Due To Multiresistant Gram Negative Bacteria
Funder
National Health and Medical Research Council
Funding Amount
$274,946.00
Summary
This fellowship application deals with the treatment of infections due to antibiotic resistant bacteria. The World Economic Forum recently discussed threats to our modern way of life. The highest ranked threats were climate change, terrorism and antibiotic resistance. During this Fellowship, two large clinical trials of treatment strategies for antibiotic resistant bacteria will be supervised by Professor Paterson.