Antibiotic resistance is a looming public health crisis. New antibiotics with new mechanisms of action are desperately needed. The long-term goal of this research is to develop new drugs that disarm bacteria to overcome the problem of antibiotic resistance.
Enhancing The Cardioprotective Effect Of Diadenosine Tetraphosphate: Designing Inhibitors Against Ap4A Hydrolase
Funder
National Health and Medical Research Council
Funding Amount
$442,500.00
Summary
Ischemia describes the condition where blood flow in the blood vessels of the heart is decreased or blocked, preventing delivery of oxygen and nutrients to the heart. Ischemic preconditioning is a phenomenon where short bursts of ischemia, followed by reperfusion, actually protect the heart from a subsequent longer period of ischemia. The biochemical signalling events involved in preconditioning are complex and incompletely defined, but most likely involve multiple pathways, although the mitocho ....Ischemia describes the condition where blood flow in the blood vessels of the heart is decreased or blocked, preventing delivery of oxygen and nutrients to the heart. Ischemic preconditioning is a phenomenon where short bursts of ischemia, followed by reperfusion, actually protect the heart from a subsequent longer period of ischemia. The biochemical signalling events involved in preconditioning are complex and incompletely defined, but most likely involve multiple pathways, although the mitochondrial ATP-dependent potassium channel may be in common with most pathways. Pretreatment with the compound diadenosine tetraphosphate (Ap4A) mimics ischemic preconditioning with noticeable reductions in tissue necrosis (cell death). This treatment has been shown in experimental work to protect the heart during periods of stress such as in heart surgery or recovery from an ischemic event. The biological site of action by Ap4A may be the mitochondria ATP-dependent potassium channel or an associated protein. Ap4A can be degraded by enzymes located inside and on the outside of heart cells, notably by two forms of Ap4A hydrolase. We will use antibody assays to understand the specific localization and amount of Ap4A hydrolase before and after ischemia and after ischemic preconditioning in human heart muscle and blood vessels. We propose to determine the structure of the enzyme and use novel computer methods to screen databases for potential inhibitors. These inhibitors of Ap4A hydrolase activity could aid the design of a potent inhibitor that would prevent Ap4A hydrolase from degrading Ap4A and therefore enhance the cardioprotective properties of Ap4A as well as minimizing side effects from the break down of Ap4A. We will also use these inhibitors and other known non-degradable Ap4A analogues in bioassays to test the relative significance of Ap4A hydrolase present in different cellular locations.Read moreRead less
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.
An Integrated Approach To Combat Antibiotic Resistance
Funder
National Health and Medical Research Council
Funding Amount
$389,120.00
Summary
The development of antibiotics such as penicillin was hailed as one of the great breakthroughs in medicine. However, an increasing number of pathogens have acquired resistance to these drugs. One of the most common resistance mechanisms employed by these pathogens is the use of metal dependent enzymes that promote the degradation of antibiotics. To date, no clinically useful inhibitors for these enzymes are available. In this project, we aim to develop such inhibitors as therapeutic drug leads.
Inhibitors Of Biotin Protein Ligase: A New Class Of Antibiotic Targetting Staphylococcus Aureus
Funder
National Health and Medical Research Council
Funding Amount
$605,963.00
Summary
The rise of drug-resistant "superbugs" is a major healthcare concern in hospitals around the world. New antibiotics are needed to combat infections caused by bacteria that are resistant to current drugs. One collaborative team of researchers is addressing this issue. They have discovered a new drug effective against Staphylococcus aureus, the cause of Golden Staph using a combination of scientific disciplines the team is now moving forward and improving their exciting new drug.
Development Of Purine Nucleoside Phosphonates As Anti-malarial Drugs Targeting Nuceloside Synthesis In Plasmodium
Funder
National Health and Medical Research Council
Funding Amount
$428,917.00
Summary
Malaria is one of the most serious infectious diseases today. Because of its location in a malaria endemic region, the tropical regions (above 19 S in latitude) of Australia face an emerging threat. The causative agent of the disease is the parasite, Plasmodium. Because of increasing resistance to existing medicines, new drugs are now needed. The drugs we will develop target the parasites replication cycle and are related in structure to those in use to treat viral infections including AIDS.
I am a protein crystallographer determining the structures of medically important proteins such as proteases. I am also a bioinformatician leading the development of informatics systems for automated highthroughput crystallography, and bioinformatic analy
Inhibitors Of Hypoxanthine-guanine-xanthine Phosphoribosyltransferase As Versatile Drugs To Treat Infectious Diseases
Funder
National Health and Medical Research Council
Funding Amount
$766,163.00
Summary
Due to the increase in resistance to many of the frontline drugs to treat bacterial and parasitic infections, there is an urgent need to develop new pipelines for drug discovery against the pathogens that are causative agents of this diseases. This project pioneers the blocking of nucleotide synthesis to develop new drug leads to treat malaria, human tuberculosis, African sleeping sickness, Chagas disease and uropathogenic E.coli infections.