Chloroquine Resistance And The Physiology Of The Malaria Parasite S Digestive Vacuole
Funder
National Health and Medical Research Council
Funding Amount
$287,921.00
Summary
Malaria is an infectious disease, caused by a single-celled parasite which invades the red blood cells of its human host. Each year, malaria causes the death of up to 3 million people, mostly children under the age of 5 The parasite has become resistant to most, if not all, of the antimalarial drugs presently available, and there is no vaccine. There is therefore an urgent need to develop new antimalarial drugs, and-or to devise strategies for overcoming the parasite s drug resistance mechanisms ....Malaria is an infectious disease, caused by a single-celled parasite which invades the red blood cells of its human host. Each year, malaria causes the death of up to 3 million people, mostly children under the age of 5 The parasite has become resistant to most, if not all, of the antimalarial drugs presently available, and there is no vaccine. There is therefore an urgent need to develop new antimalarial drugs, and-or to devise strategies for overcoming the parasite s drug resistance mechanisms. Chloroquine was, for many years, the mainstay of antimalarial chemotherapy and was, in many senses, a 'wonder-drug' cheap, safe and effective. However the emergence and spread of parasites that are resistant to chloroquine has meant that the drug is now largely useless as an antimalarial. Chloroquine kills (sensitive) parasite through an effect on the parasite s digestive vacuole an internal acidic compartment in which the parasite breaks down protein taken up from its host red blood cell. This compartment plays a crucial role in the growth and proliferation of the parasite. Yet we understand very little about its basic physiology, and nor do we understand the mechanism by which chloroquine-resistant parasites are able to survive exposure to the drug. The aim of the work proposed here is to gain an increased understanding of some of the mechanisms underlying the physiology of the parasite s digestive vacuole, as well as some of the factors influencing the accumulation of chloroquine within this compartment. The former part of the work may well reveal new antimalarial drug targets. The latter part of the work will increase our understanding of the mechanism of chloroquine resistance, thereby laying the groundwork for strategies by which these mechanisms might be circumvented and chloroquine-related drugs thereby restored to the front-line of our ongoing and increasingly desperate fight against malaria.Read moreRead less
Ion Transport In The Malaria Parasite, Plasmodium Falciparum
Funder
National Health and Medical Research Council
Funding Amount
$225,721.00
Summary
Malaria is an infectious disease caused by single-cell protozoan parasites which, during the course of their complex lifecycle, invade the red blood cells of their human hosts. In recent years the emergence and spread of malaria parasites with high levels of antimalarial drug resistance has given rise to the very real possibility that within a few years, there will be large parts of the world in which malaria is an untreatable disease. There is therefore an urgent need for new antimalarial drugs ....Malaria is an infectious disease caused by single-cell protozoan parasites which, during the course of their complex lifecycle, invade the red blood cells of their human hosts. In recent years the emergence and spread of malaria parasites with high levels of antimalarial drug resistance has given rise to the very real possibility that within a few years, there will be large parts of the world in which malaria is an untreatable disease. There is therefore an urgent need for new antimalarial drugs. Despite the enormous clinical significance of the malaria parasite, the basic physiology of this organism is not understood. Pathways involved in ion balance, in the uptake of essential nutrients and in the release of potentially toxic waste products all play a crucial role in the survival of the parasite and are potential chemotherapeutic targets. However the properties of these pathways are, as yet, largely unknown. This work will provide fundamental (and pharmacological) information about these pathways. It will thereby open up exciting new possibilities with regard to the chemotherapy of malaria and will provide a rational basis for a strategy in which these pathways might be exploited as antimalarial drug targets.Read moreRead less
Metabolomic Analysis And Membrane Transport Proteins In The Malaria Parasite
Funder
National Health and Medical Research Council
Funding Amount
$368,875.00
Summary
The malaria parasite is a single celled organism which invades the red blood cells of those it infects. There is no vaccine and the parasite is becoming increasingly resistant to the drugs that we have available. There is therefore an urgent need for new antimalarial strategies. Research in this area has been helped by the sequencing of the genome of the parasite. However we still don t know what most of the genes in the parasite do, and it is not a straightforward matter to find out. One of the ....The malaria parasite is a single celled organism which invades the red blood cells of those it infects. There is no vaccine and the parasite is becoming increasingly resistant to the drugs that we have available. There is therefore an urgent need for new antimalarial strategies. Research in this area has been helped by the sequencing of the genome of the parasite. However we still don t know what most of the genes in the parasite do, and it is not a straightforward matter to find out. One of the things hampering us in our efforts to develop new antimalarial drugs is our relatively poor understanding of the sorts of biochemical pathways that the parasite relies on to support its high rate of growth and replication inside the red blood cell, as well the biochemical mechanisms that enable it to becomes drug-resistant. In this study we will use a range of modern analytical techniques to carry out the first detailed survey of the biochemical composition - the so-called metabolome - of the parasite. We will investigate how this changes in response to nutrient deprivation, in response to mutations in genes which play a key role in antimalarial drug resistance and in response to changes in the expression of genes encoding proteins which we believe to be involved in the uptake of nutrients by the parasite. This project will provide us with a wealth of new information about the biochemical make-up of the parasite, and it will provide new insights into the biochemical pathways that are operating and which might be targeted with new drugs. The work is likely to provide new insights into mechanisms of antimalarial drug resistance. It will also form the basis for a strategy that is likely to be extremely useful in helping us to ascribe function to the many genes involved in the biochemistry of this important human pathogen.Read moreRead less
Understanding The Development And Spread Of Pan Resistance In Acinetobacter Baumannii
Funder
National Health and Medical Research Council
Funding Amount
$2,339,215.00
Summary
Resistance to all antibiotics available for treatment of bacterial infections is a cause for global concern (Word Health Organization, US Centres for Disease Control) as it also compromises therapies relying on antibiotics such as transplantation and cancer chemotherapy. Extensively antibiotic resistant Acinetobacter baumannii, mainly causes hospital-acquired infections. This project will seek to track different types of these bacteria as they repeatedly spread around the world.
Molecular Epidemiology Of Antibiotic Resistant Salmonella Enterica Strains Causing Human Disease
Funder
National Health and Medical Research Council
Funding Amount
$493,767.00
Summary
Salmonella infections are responsible for a substantial proportion of reported food poisoning cases caused by bacteria and many of these infections are due to antibiotic resistant strains. Infections caused by antibiotic resistant organisms are hard to treat and generally more severe, of longer duration, and result in longer hospital stays. These strains are mostly acquired from foods, e.g. meats, dairy products, poultry, eggs, and other contaminated food products but can also be derived from ot ....Salmonella infections are responsible for a substantial proportion of reported food poisoning cases caused by bacteria and many of these infections are due to antibiotic resistant strains. Infections caused by antibiotic resistant organisms are hard to treat and generally more severe, of longer duration, and result in longer hospital stays. These strains are mostly acquired from foods, e.g. meats, dairy products, poultry, eggs, and other contaminated food products but can also be derived from other sources. Salmonella strains harboured by food-producing animals are the source of most of the food contamination.Tracing the source of individual resistant strains is essential for eradication and as there are many Salmonella types, some of which are found associated only with specific animals or birds, accurate identification is needed. The proposed work will make this process more accurate by using molecular techniques to unequivocally establish suspected connections and reveal further ones that are difficult to discern using current data and methods. This should decrease the number of infections due to resistant strains.Read moreRead less
Antibiotic resistance increases mortality and costs in the Intensive Care Unit (ICU), but the impact of antibiotic therapy has not been adequately studied. We propose to characterise the behaviour of key elements of the bacterial microflora (resistant bacteria and major resistance genes) in response to antibiotics. We have developed new rapid diagnostics to harness these data and this proposal has the potential to greatly improve diagnostic speed and accuracy and thus clinical outcomes.
Plasmodium Knowlesi As A Genetic Model For Plasmodium Vivax Drug Resistance
Funder
National Health and Medical Research Council
Funding Amount
$417,193.00
Summary
Two different Plasmodium parasites cause the majority of malaria worldwide. However, one type, P. vivax, is unable to be cultured in the laboratory and therefore has been poorly studied. Drug resistance has been observed but the underlying causes are poorly understood. We propose to use a closely related parasite, P. knowlesi, as a model to understand drug resistance mechanisms. This knowledge will be used to follow resistance in the field and direct policy of the most appropriate treatment.
Novel Membrane-targeted Antibiotics Against Drug-resistant Gram-positive Bacterial Infections
Funder
National Health and Medical Research Council
Funding Amount
$1,351,496.00
Summary
This project aims to develop a best in class antibiotic, Vancapticin, with superior efficacy, broader spectra of action and improved therapeutic index than existing therapies for Gram-positive (G+ve) bacterial infections. The research team has identified lead candidates that offer equivalent &/or superior potency, efficacy & pharmacokinetic profiles compared to several clinical comparators. NHMRC Development funding is required to select a candidate for an Investigative New Drug application.
A New Mechanism For Transposition Of Antibiotic Resistance Genes
Funder
National Health and Medical Research Council
Funding Amount
$501,839.00
Summary
Understanding how antibiotic resistance genes are acquired by bacteria is important if we are to understand how bacteria become resistant in so many antibiotics, limiting treatment options. This project will investigate the way a family of insertion sequences captures and then moves resistance genes. This mechanism contributes to resistance in many bacterial pathogens including ones that are resistant to many different antibiotics.
Antimicrobial Stewardship - Establishing Effective Programs For Australian Hospitals
Funder
National Health and Medical Research Council
Funding Amount
$1,232,361.00
Summary
This project will examine strategies to improve the use of antimicrobial drugs in Australian hospitals. It will evaluate the impact of antimicrobial stewardship programs on antibiotic prescribing practices in Victorian tertiary hospitals and determine the organisational factors associated with success. It will also examine the needs, and establish models for antimicrobial stewardship beyond the tertiary hospital setting, in private hospitals, small metropolitan and rural hospitals.