Ecto-nucleoside Triphosphate Diphosphohydrolases Of Leishmania: Role In Virulence And Potential As Antimicrobial Targets
Funder
National Health and Medical Research Council
Funding Amount
$314,658.00
Summary
Leishmaniasis is a serious disease that affects millions of people worldwide, particularly in developing countries. The disease is caused by a number of species of parasites, and current treatment regimes are not ideal. This research aims to target certain proteins produced by the parasite and define the role of the proteins in causing disease. Furthermore this research will identify new drugs that will block these parasite proteins and may contribute to new therapies for this serious disease.
Investigating The Utility Of Therapeutic Drug Monitoring Of Beta-lactam Antibiotics In Hospitalised Patients
Funder
National Health and Medical Research Council
Funding Amount
$215,887.00
Summary
The appropriate dosing of antibiotics for patients admitted to hospital is based on broad guidelines derived from studies in healthy volunteers or in patients that may have different types of infections. Minor changes in the clinical state of the patients can require significant dosing adjustments. The best way to guarantee appropriate antibiotic therapy is to individualize doses based on blood concentration data. We aim to determine the utility of dose adjustment in hospitalized patients.
Functional And Structural Studies Of A Glycosyltransferase Essential For Complex Glycolipid Biosynthesis In Mycobacteria
Funder
National Health and Medical Research Council
Funding Amount
$508,838.00
Summary
Tuberculosis (TB) kills more than three million people each year while the causative bacterial species, Mycobacterium tuberculosis, infects one-third of the entire human population. An alarmingly high rate of TB exists in Australia's indigenous population. This proposal aims to identify and characterise essential processes involved in synthesis of the outer coat of the bacterium which are potential targets for new drugs for the treatment of this devastating disease.
SiRNA Induced TGS Of Retroviruses: Elucidation Of Underlying Mechanisms And Their Application In Animal Models
Funder
National Health and Medical Research Council
Funding Amount
$371,502.00
Summary
AIMS To elucidate changes in DNA that accompany suppression of HIV growth caused by certain unusual RNA molecules that turn off the ability of HIV to reproduce and make the virus dormant within the infected cell. While we have discovered RNA molecules that can do this to HIV in the test tube, we wish to develop similar molecules that can be used in animal models, so that we can decide whether this technology can be developed for use in humans. We also wish to understand more clearlky the mechani ....AIMS To elucidate changes in DNA that accompany suppression of HIV growth caused by certain unusual RNA molecules that turn off the ability of HIV to reproduce and make the virus dormant within the infected cell. While we have discovered RNA molecules that can do this to HIV in the test tube, we wish to develop similar molecules that can be used in animal models, so that we can decide whether this technology can be developed for use in humans. We also wish to understand more clearlky the mechanisms underlying this effect. BACKGROUND These RNA molecules can suppress a range of pathogenic human viruses including HIV-1 in the test tube. Our novel approach appears to induce changes that are long lasting and are less susceptible to mutations by the virus that allow it to become resistant to other therapeutic strategies. RESEARCH PLAN Initially more work will be done in tissue culture to determine the optimal design of these molecules and the best way to administer them. The most promising of these designs will be tested in small groups of infected animals as a preliminary demonstration of efficacy. In parallel experiments will be performed to elucidate the mechanisms undelying the suppressive effects of these molecules. OUTCOMES AND SIGNIFICANCE This work will lead to a significant increase in our understanding of the way replication of HIV is regulated and will develop a promising new therapeutic strategy for this virus that may be applicable to other conditions.Read moreRead less
Targeting The Mannose Activation Pathway In Leishmania - Novel Drug Targets And Vaccines.
Funder
National Health and Medical Research Council
Funding Amount
$338,661.00
Summary
Leishmaniasis is a parasitic disease ranging in severity from skin lesions to fatal systemic infection. It is a serious public health problem throughout many regions of the world. Co-infection with HIV has emerged as a serious problem in Africa, South America and southern Europe. Recently, leishmaniasis has been identified in East Timor and in kangaroos in Australia. Treatment of leishmaniasis is based on chemotherapy, but currently used drugs are expensive, have high toxicity and unwanted side ....Leishmaniasis is a parasitic disease ranging in severity from skin lesions to fatal systemic infection. It is a serious public health problem throughout many regions of the world. Co-infection with HIV has emerged as a serious problem in Africa, South America and southern Europe. Recently, leishmaniasis has been identified in East Timor and in kangaroos in Australia. Treatment of leishmaniasis is based on chemotherapy, but currently used drugs are expensive, have high toxicity and unwanted side effects. They have also been compromised by the emergence of resistance in the parasite. Leishmania synthesises a range of surface molecules, which are needed for virulence and parasite survival in the host. The biosynthesis process of these molecules requires activated mannose. We have identified two novel parasite genes encoding for enzymes, which are essential for the biosynthesis of surface virulence factors. When either of these genes is deleted the parasite can no longer cause disease. This suggests that drugs targeting the two enzymes will be able to control the infection. We will produce crystals of these enzymes and solve their 3D structure using state of the art technology to screen libraries of synthetic chemicals to find candidate inhibitors of enzyme activity. When these compounds are identified we will use computer modelling to design compounds based on these inhibitors and crystal structure, which will lead to a new generation of anti-Leishmania drugs. We will also determine whether the avirulent parasites can be used as an attenuated vaccine. Recovery from infection leads to a solid immunity and protection from subsequent infection indicating that vaccination is feasible, but despite of a huge amount of research there is no antileishmanial vaccine currently available. This study will lead to potential novel antileishmanial drugs and vaccines. It will also provide fundametal new knowledge of the structure of enzymes critical for parasite virulence.Read moreRead less
Antiviral compounds to inhibit the replicase of hepatitis C virus. Hepatitis C virus is a major public health problem. There are currently 200,000 infected individuals in Australia and 16,000 new infections every year. There is no specific treatment and current therapy treats a small percentage of patients only, which consists of interferon-alpha and ribavirin. This results in side effects and only a 50% cure rate. This study's outcomes are expected to lead to greater access to treatment and imp ....Antiviral compounds to inhibit the replicase of hepatitis C virus. Hepatitis C virus is a major public health problem. There are currently 200,000 infected individuals in Australia and 16,000 new infections every year. There is no specific treatment and current therapy treats a small percentage of patients only, which consists of interferon-alpha and ribavirin. This results in side effects and only a 50% cure rate. This study's outcomes are expected to lead to greater access to treatment and improved therapy resulting in higher cure rates and in a dramatic reduction in the cost of treating patients. A novel therapy will provide considerable benefits for the national biotechnology industry.Read moreRead less
Production And In Vivo Delivery Of Bacteriphage Lytic Enzymes By Lactobacillus Fermentum For Disease Prevention.
Funder
National Health and Medical Research Council
Funding Amount
$272,250.00
Summary
Lactic acid bacteria are commonly found in the oral cavity, digestive and female urogenital tracts of humans and other mammals. They are almost completely harmless with only some streptococci and enterococci being able to cause disease. The harmless lactic acid bacteria are mainly classified as Lactobacillus or Lactococcus, and members of of these groups are used in the manufacture of dairy foods such as yoghurt and cheese. Lactobacilli in particular are marketed in a number of health-promoting ....Lactic acid bacteria are commonly found in the oral cavity, digestive and female urogenital tracts of humans and other mammals. They are almost completely harmless with only some streptococci and enterococci being able to cause disease. The harmless lactic acid bacteria are mainly classified as Lactobacillus or Lactococcus, and members of of these groups are used in the manufacture of dairy foods such as yoghurt and cheese. Lactobacilli in particular are marketed in a number of health-promoting or probiotic foodstuffs which are consumed all over the world. We are interested in developing lactobacilli into therapeutic agents which will prevent or treat infections caused by a range of harmful bacteria including the bacteria which cause strep throat and food poisoning. Lactobacilli will be genetically modified to produce enzymes which specifically kill harmful bacteria. These enzymes are from viruses which infect specific bacteria. Using animal models the modified lactobacilli or lactobacilli produced enzymes will be administered orally and tested for their ability to treat possible infections caused by pathogenic bacteria in the oral cavity and intestine. This new therapeutic production and delivery system offers an alternative infectious disease control method to antibiotics. This agent may also be used to control some of the antibiotic-resistant bacteria that are of significant worldwide concern.Read moreRead less