Evaluation Of Naturally Occurring Resistance To Direct Acting Antiviral Drugs (DAAs) In Individuals With Acute Hepatitis C Infection
Funder
National Health and Medical Research Council
Funding Amount
$333,778.00
Summary
Hepatitis C therapy in the future is likely to involve the use of Directly Acting Antivirals, which offer a better chance of treatment success and shorter treatment courses. The downside to these new agents is the possible development of drug resistance. Studies suggest that drug resistant strains may already exist in some individuals prior to treatment. This study plans to use sensitive methods to examine how common drug resistant strains are in untreated individuals with acute hepatitis C.
Molecular Mechanisms Of Ivermectin Resistance In The Ectoparasitic Mite, Sarcoptes Scabiei
Funder
National Health and Medical Research Council
Funding Amount
$289,561.00
Summary
A largely neglected parasitic disease, scabies is a significant disease of children, particularly in remote Aboriginal communities in northern Australia. The recent emergence of ivermectin resistance threatens future control of scabies. This research explores the genetic basis of ivermectin resistance in the scabies mite, developing molecular markers to identify the emergence of resistance in the community, leading to improved tools for resistance management and sustainable treatment strategies.
Using The Information Inherent In Immune Responses To Design Vaccines
Funder
National Health and Medical Research Council
Funding Amount
$526,571.00
Summary
The parts of viruses, bacteria and of cancer cells that are recognised by the immune system are called epitopes. Epitopes are generated from these agents by dendritic cells which are found in many parts of the body where they act as sentinels on the look out for dangerous organisms. Epitopes are very small pieces of the proteins against which immune responses are mounted and can be readily synthesised in the laboratory. If we were to design vaccines that are made of epitopes such that the immune ....The parts of viruses, bacteria and of cancer cells that are recognised by the immune system are called epitopes. Epitopes are generated from these agents by dendritic cells which are found in many parts of the body where they act as sentinels on the look out for dangerous organisms. Epitopes are very small pieces of the proteins against which immune responses are mounted and can be readily synthesised in the laboratory. If we were to design vaccines that are made of epitopes such that the immune response is focussed to those exact regions of infectious agents it could lead to an immune response that eliminates the agent. The problem is, however, that we usually do not know which part of the virus, bacterium or cancer cell is recognised as an epitope. So the identification of epitopes is a limitation to the design of epitope-based vaccines. Anyone who has encountered a virus, bacterium or tumour cell and who has raised an immune response will have developed antibodies and immune cells able to recognise the right parts of the infectious agent or cancer cell. These antibodies and immune cells now contain information about the epitopes. We will use antibodies and blood cells obtained from people immune to the disease to extract epitopes from a panel of protein fragments that represent the agent against which we wish to make vaccines. These newly discovered epitopes will then be incorporated into totally synthetic vaccines. These vaccines will also incorporate a simple lipid molecule which specifically targets and activates the dendritic cell that is key for the induction of potent immune responses. All of the technologies we propose are in place and we have proof of principle that the approach leads to the successful design of vaccines that are effective against infectious diseases and cancers.Read moreRead less
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
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
Sensitive, Rapid And Accurate Detection Of The Emergence Of Neuraminidase Inhibitor Resistance By Real-time PCR, LCR And
Funder
National Health and Medical Research Council
Funding Amount
$118,875.00
Summary
An influenza pandemic causing by highly pathogenic H5N1 virus may occur in the near future. As a vaccine for H5N1 will not be available in the foreseeable months, antiviral drugs are the only possible choice for prophylaxis and treatment. Currently only two drugs have been clinically proven to be effective against H5N1 strain and the emergence of drug resistant in H5N1 influenza virus has been reported which may significantly hamper the treatment. Understanding and monitoring the emergence of th ....An influenza pandemic causing by highly pathogenic H5N1 virus may occur in the near future. As a vaccine for H5N1 will not be available in the foreseeable months, antiviral drugs are the only possible choice for prophylaxis and treatment. Currently only two drugs have been clinically proven to be effective against H5N1 strain and the emergence of drug resistant in H5N1 influenza virus has been reported which may significantly hamper the treatment. Understanding and monitoring the emergence of these drug resistant strains during local spreading will be critical in managing an H5N1 influenza pandemic in Australia. In the proposed project, we will develop important diagnostic tools using our world leading Rolling Circle Amplification (RCA) technology for the monitoring of the development and possible transmission of drug resistant influenza strains. Upon finishing the project, at lease three sensitive diagnostic methods will be developed for the detection of the emergence of drug resistance at the very early stage.Read moreRead less
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.
Optimisation Of Antimicrobial Therapy For Severe Bacterial Infections In Neonates And Young Children In Papua New Guinea
Funder
National Health and Medical Research Council
Funding Amount
$943,865.00
Summary
This study aims to provide important information on the way young Papua New Guinean children with serious bacterial infections handle antibiotics, including newer agents that may be required if bacterial resistance is confirmed or increases. The data will be used to optimise treatment, thus reducing mortality and potential adverse drug effects, in PNG nad other tropical countries, and may have implications for the developed world as well.
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.