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.
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.
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
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.
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.