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.
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.
The Biosynthesis Of Mycobactin T, A Virulence Factor From Mycobacterium Tuberculosis.
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
Mycobacterium tuberculosis is the causative agent of tuberculosis. The drug isoniazid led to a dramatic and sustained decline in mortality due to tuberculosis. This led to it being described in medical literature in 1988 as a disappearing disease which was now fairly easy to treat. However, the advent of HIV and the rapid rise of multidrug resistant M. tuberculosis led to dramatic changes. The risk that an HIV infected individual will develop active tuberculosis is 7% per year, compared to a lif ....Mycobacterium tuberculosis is the causative agent of tuberculosis. The drug isoniazid led to a dramatic and sustained decline in mortality due to tuberculosis. This led to it being described in medical literature in 1988 as a disappearing disease which was now fairly easy to treat. However, the advent of HIV and the rapid rise of multidrug resistant M. tuberculosis led to dramatic changes. The risk that an HIV infected individual will develop active tuberculosis is 7% per year, compared to a lifetime risk of 10% for an immunocompetent person. Similarly, the prevalence of drug resistant strains of M. tuberculosis is over 5% in many regions, including SE asia. Mycobacterial infections are regarded as the leading cause of morbidity and mortality world wide and WHO estimates that 30 million deaths will occur in the next decade due to these infections. Clearly, new drugs are required to combat the rising menace of this organism. The aim of this project is to detail the unique metabolic pathways in M. tuberculosis that produce Mycobactin T, essential to the virulence of this organism. Mycobactin T helps the bacteria obtain iron, an essential nutrient. These factors make the mycobaction pathway an ideal drug target and an understanding of its biochemistry is essential to its eventual exploitation for intervention in M. tuberculosis infections. We hypothesise that it may already provide the unknown site of action of a clinically employed, antituberculosis drug para-aminosalicylate (PAS). This project will i) fully define the structure of mycobactin T; ii) clone and overexpress key genes which catalyse the first three steps of mycobactin formation; iii) purify and characterise the overexpressed proteins with respect to their biochemical function; iv) examine the interaction of PAS with the proteins likely to be targeted by this antimycobacterial agent. The results of this work will provide the basis for the development of future anti-tuberculosis drugs.Read moreRead less
Flaviviral Proteases As Viable Targets For Antiinfective Drugs
Funder
National Health and Medical Research Council
Funding Amount
$620,716.00
Summary
Viruses hijack the machinery and nutrients of cells they infect in order to reproduce. We will study viral enzymes (proteases) essential for virus replication, use fluorescent probes to learn where the viral enzymes hide and act in infected cells, track the passage of drugs aimed at these enzymes, design drugs to block their actions and stop virus replication, and test antiviral activity against Dengue, West Nile, Japanese Encephalitis and Yellow Fever viruses which infect millions of people.
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.
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.
The West Nile Viral Protease, NS3: A Target For Antiviral Drug And Vaccine Design
Funder
National Health and Medical Research Council
Funding Amount
$230,500.00
Summary
The West Nile Virus (WNV) was first isolated from a woman in the West Nile region of Uganda in 1937. It is one of ~70 known flaviviruses (e.g. Dengue fever, Yellow fever, West Nile, Kunjun, Japanese encephalitis, St. Louis encephalitis, tick-borne encephalitis, Australian encephalitis and the related hepatitis C virus) which annually infect hundreds of millions of people worldwide, particularly in tropical and sub-tropical areas, and cause major public health problems. WNV is endemic in the Midd ....The West Nile Virus (WNV) was first isolated from a woman in the West Nile region of Uganda in 1937. It is one of ~70 known flaviviruses (e.g. Dengue fever, Yellow fever, West Nile, Kunjun, Japanese encephalitis, St. Louis encephalitis, tick-borne encephalitis, Australian encephalitis and the related hepatitis C virus) which annually infect hundreds of millions of people worldwide, particularly in tropical and sub-tropical areas, and cause major public health problems. WNV is endemic in the Middle East, parts of Africa and Europe, but recent epidemics in Israel (1998), Romania (1996), United States (1999), and UK (2003) have been characterized by severe symptoms , severe neurological pathology, and fatalities. In the USA alone there were 4,156 infections and 284 deaths in 2002, 9122 infections and 223 deaths in 2003, and this mosquito borne virus has quickly spread since 1999 through all USA states and into Canada and Mexico (http:--www.cdc.gov-ncidod-dvbid-westnile-index.htm). No treatments or vaccines are available. This project focuses on an enzyme, known as the West Nile Virus NS3 protease, that is essential for replication of the virus. By studying the enzyme in the laboratory we can design small molecules that can block its function and these have real potential as leads for development of drug treatments for people infected by this virus. A precedent is the success of inhibitors of HIV-1 protease that are the most effective treatment for humans with HIV-infections. Our studies will also be used to develop potential vaccines. The science involves experts on protease enzymes, drug design and development, virology including West Nile virology, and vaccine development. We expect to generate drug and vaccine candidates and new information for their development that is at the cutting edge of West Nile Virus research.Read moreRead less
Targeting Acetohydroxyacid Synthase To Discover New Antifungal Agents.
Funder
National Health and Medical Research Council
Funding Amount
$481,135.00
Summary
Invasive fungal infections are increasingly being recognized as a major life threatening risk to hospitalized patients. The efficacy of the current medications is sub-optimal due to the emergence of resistance and the high dosage regimes that are required to treat these infections. We propose to develop a new class of antifungal agent that target an enzyme, acetohydroxyacid synthase, whose activity is required for the survival of pathogenic fungi in mammals.