Preventing The Evolution Of Transmissible Nitroimidazole Resistance In Mycobacterium Tuberculosis
Funder
National Health and Medical Research Council
Funding Amount
$664,463.00
Summary
Tuberculosis kills more people than any other infectious disease. Unfortunately, the drugs available to us to treat TB are losing their efficacy due to the evolution of drug resistance. A new class of drugs, nitroimidazoles, has been developed, but there is a risk that the bacterium that causes TB will develop resistance to these compounds too. We will identify resistance mutations before they occur in the wild, to help identify them and find new compounds for which resistance cannot develop.
DsbA Foldases From Multidrug Resistant Pathogens As Targets For New Antimicrobials
Funder
National Health and Medical Research Council
Funding Amount
$743,401.00
Summary
Bacteria that cause common human infections, such as cystitis and diarrhoea, are now resistant to many antibiotics. If no action is taken, by 2050 antibiotic resistant infections will kill more people each year than cancer. This project aims to address this global public health crisis by characterising promising new bacterial targets and inhibitors designed to disarm multidrug resistant pathogens. Longer term this work could provide new infection therapies that are urgently needed.
Discovery Of Active Metabolic Pathways Suitable For Drug Targeting In Trypanosoma Brucei
Funder
National Health and Medical Research Council
Funding Amount
$485,517.00
Summary
Sleeping Sickness is a parasitic disease affecting many of the world’s poorest countries, and is fatal if left untreated. The aim of this project is to identify new metabolic pathways in the parasite that causes Sleeping Sickness, and to investigate how drugs interfere with parasite metabolism. This will provide the basis for new drug discovery efforts and facilitate the development of new medicines for Sleeping Sickness.
Investigation Of Neuregulin Precessing By Beta-site APP Cleaving Enzyme And Gamma Secretase In Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$46,715.00
Summary
Schizophrenia (SCZ) is a complex psychiatric disorder that appears in male and female around adulthood. To date there is no clear pathological symptoms to identify SCZ individuals and place them in a specific group. Some proteins are genetically associated with this disease. I will investigate how some of these proteins disturb the function of the brain in human. My recent published data shows decrease of one of the proteins in the brain of SCZ group. My project may help develop novel and more s ....Schizophrenia (SCZ) is a complex psychiatric disorder that appears in male and female around adulthood. To date there is no clear pathological symptoms to identify SCZ individuals and place them in a specific group. Some proteins are genetically associated with this disease. I will investigate how some of these proteins disturb the function of the brain in human. My recent published data shows decrease of one of the proteins in the brain of SCZ group. My project may help develop novel and more selective therapies with less side-effects.Read moreRead less
ADAMTS-5 Activity And The Effect Of A Dominant-negative Mutant
Funder
National Health and Medical Research Council
Funding Amount
$540,235.00
Summary
Cartilage loss is a feature of arthritis and is caused by enzymes. We discovered that loss of a critical cartilage component is caused by the enzyme ADAMTS-5. We also discovered that a mutant form of ADAMTS-5 blocks the normal emzyme, possibly by a novel binding interaction. If we can understand how this interaction works, we can exploit it for the design of new arthritis therapies. This project aims to identify the novel interaction and improve out understanding of cartilage destruction.
How Important Is Collagen Destruction In Arthritis? A Study With Collagenase-resistant Knockin Mice
Funder
National Health and Medical Research Council
Funding Amount
$529,723.00
Summary
Aggecan and collagen are important structural molecules in cartilage. Together they allow cartilage to bear weight and resist compression. In arthritis, collagen is degraded by collagenases and aggrecan is degraded by aggrecanases. Aggrecan loss is a feature of cartilage disease. Early aggrecan loss is well documented and usually precedes clinical symptoms, suggesting that it is the initiating step in cartilage pathology. Aggrecan loss precedes collagen damage in explant culture, however it is n ....Aggecan and collagen are important structural molecules in cartilage. Together they allow cartilage to bear weight and resist compression. In arthritis, collagen is degraded by collagenases and aggrecan is degraded by aggrecanases. Aggrecan loss is a feature of cartilage disease. Early aggrecan loss is well documented and usually precedes clinical symptoms, suggesting that it is the initiating step in cartilage pathology. Aggrecan loss precedes collagen damage in explant culture, however it is not known whether inhibiting aggrecanases is sufficient to block cartilage damage long-term. In contrast, other studies suggest that aggrecan is only lost after damage to the collagen scaffold. These studies propose that clipping of the collagen scaffold may initiate aggrecan release; with progressive degeneration and collagen clipping, more aggrecan is lost, until ultimately the scaffold is severely damaged and aggrecan is severely depleted. Cartilage can only withstand a limited degree of collagen degradation and any significant damage to the network is widely considered to be irreparable. It is unclear what role aggrecanases and collagenases have in initiating and perpetuating cartilage damage. We have mice with aggrecan resistant to aggrecanases and mice with inactive aggrecanase. We will also create mice with collagen resistant to collagenase. We will use these mice to determine the contribution of collagenases and aggrecanases to the initiation and progression of cartilage damage, in three models of joint disease. We will identify differences in time of disease onset, rate of disease progression and disease severity. The results will show whether one or both activities is important for the initiation and progression of joint disease. This will reveal whether single or combination therapies are required for the management of arthritis. The research will inform the pharmaceutical industry on directions for the development of new drugs to prevent joint disease.Read moreRead less
A group of nerves, called sensory nerves, supply most body organs including the uterus, and are well known to transmit information to the brain. It is now known that these nerves are also capable of releasing the chemicals (neuropeptides) from their endings within these body organs to affect their function. In the uterus these chemicals cause the uterus to contract. We have shown that neuropeptides known as tachykinins are effective in lower concentrations when applied to small specimens of uter ....A group of nerves, called sensory nerves, supply most body organs including the uterus, and are well known to transmit information to the brain. It is now known that these nerves are also capable of releasing the chemicals (neuropeptides) from their endings within these body organs to affect their function. In the uterus these chemicals cause the uterus to contract. We have shown that neuropeptides known as tachykinins are effective in lower concentrations when applied to small specimens of uterine tissue taken from non-pregnant women at hysterectomy than when applied to similar uterine specimens taken from pregnant women at caesarean section. The aim of this project is twofold. Firstly, we want to know why the tachykinins are more potent in uterine tissue from non-pregnant women. Possible explanations that we will examine are that tissues from non-pregnant women contain more sites of action at which the peptides can act, or alternatively, that there is decreased breakdown of these tachykinins in uterine tissue from non-pregnant women. This could occur if a substance known to break down the tachykinins in the uterus shows greater activity during pregancy than when a woman is not pregnant. Secondly, we wish to find out if other chemicals (substances that can produce inflammatory responses, and in particular a group of chemicals known as prostaglandins), that are known to be present in greater amounts in the tissues of women during disease states such as dysmenorrhoea, can cause the release of the neuropeptides that we are studying. If they do cause such a release of tachykinins, this could be an important factor contributing to the disease state. Our hypothesis is that tachykinins and the substances which can break them down may play an important role in regulating uterine contractility in non-pregnant and to a lesser degree in pregnant women.Read moreRead less
Structure-based Design Of Inhibitors Of PimA - A New Target For Tuberculosis Therapy
Funder
National Health and Medical Research Council
Funding Amount
$666,246.00
Summary
Tuberculosis (TB) is a devastating disease that kills 2 million people worldwide each year and affects one-third of the entire human population. Bacterial resistance to existing antibiotics is an ever increasing problem, highlighting the need to develop new anti-TB drugs. The aim of this project is to develop specific inhibitors to target a protein that is essential for the survival of the tuberculosis bacterium.
Silent Mutations In The HIV-1 Reverse Transcriptase Selected During Antiretroviral Therapy
Funder
National Health and Medical Research Council
Funding Amount
$555,325.00
Summary
This project seeks to determine the role of silent mutations in the HIV reverse transcriptase that are selected during drug therapy in HIV infected individuals on HIV fitness, reverse transcriptase function and the emergence of drug resistance. This study will increase our understanding of the mechanisms by which the virus evades the effects of antiretrovirals and will provide a rationale for deciding on the best drug combinations for use in patients infected with specific HIV strains (clades).
Broad Spectrum Inhibition Of An Enzyme Antibiotic Target
Funder
National Health and Medical Research Council
Funding Amount
$321,534.00
Summary
There is a well-documented need to replenish the antibiotic pipeline with new products to combat the rise of drug resistant bacteria. In this project, the enzyme dihydrodipicolinate synthase (DHDPS) is targetted which is essential to bacterial viability. A number of independent but synergistic drug discovery approaches are investigated to develop and test DHDPS inhibitors in the pursuit of a novel class of antibiotics.