Protecting The Efficacy Of Antimalarial Therapies With Novel Approaches To Suppress The Emergence Of Drug Resistance
Funder
National Health and Medical Research Council
Funding Amount
$408,768.00
Summary
The global campaign to eliminate malaria is under serious threat from the continuing emergence and spread of Plasmodium falciparum parasites resistant to antimalarial drugs. However in acquiring resistance to one drug, the parasite can become more susceptible to other antimalarials. This project aims to 1) test the ability of drug pairs with opposing selection forces to suppress resistance in vitro and 2) define the physiological and molecular basis of these opposing evolutionary forces.
Determining The Mechanistic Basis Of The Patterns Of Inverse Drug Susceptibility Induced By Two Key Drug Resistance Proteins Of The Malaria Parasite.
Funder
National Health and Medical Research Council
Funding Amount
$567,273.00
Summary
The inexhaustible capacity of many pathogens and cancers to develop resistance to new drugs is a serious threat to world health. Yet in acquiring resistance to one drug, many pathogens and cancer cells become hypersensitive to one or more other drugs. We seek to elucidate several of the molecular mechanisms underpinning this phenomenon in the malaria parasite. Insights gained from this work will contribute to the formulation of new therapeutic strategies that overcome or retard drug resistance.
Dissecting The Interactions Of Antimalarial Drugs With The Two Key Determinants Of Drug Resistance In The Malaria Parasite - The 'chloroquine Resistance Transporter' And The 'multidrug Resistance Transporter 1'
Funder
National Health and Medical Research Council
Funding Amount
$415,218.00
Summary
The malaria parasite is a single-celled organism which invades the red blood cells of its host. The aim of this fellowship is to study two proteins that are central to the parasite’s ability to evade the toxic effects of a number of drugs. The parasite's susceptibility to chloroquine, and other drugs, is altered by small changes in these proteins. This work will advance our understanding of the increasingly widespread phenomenon of antimalarial drug resistance, and of how it may be overcome.
The Na+-H+ Exchanger And H+-pumping Pyrophosphatases Of The Malaria Parasite
Funder
National Health and Medical Research Council
Funding Amount
$664,604.00
Summary
Malaria is an infectious disease caused by a single-celled parasite. The disease kills up to 2 million people each year and the parasite is becoming increasingly resistant to available drugs. This work focuses on the mechanisms by which the parasite controls its internal ion concentrations. These mechanisms may be new drug targets, and they may also play a role in antimalarial drug resistance. For both of these reasons it is important that we understand them.
Interactions Between The Malaria Parasite's Chloroquine Resistance Transporter And Antimalarial Drugs
Funder
National Health and Medical Research Council
Funding Amount
$485,641.00
Summary
The malaria parasite is a single-celled organism which invades the red blood cells of its host. The aim of this project is to characterize the parasite protein responsible for conferring resistance to chloroquine, and to study its interaction with other antimalarial drugs. The parasite's susceptibility to chloroquine, and other drugs, is altered by small changes in this protein. This work will advance our understanding of the increasingly widespread phenomenon of antimalarial drug resistance.
Targeting An Ion Pump In The Malaria Parasite With Multiple Compound Classes
Funder
National Health and Medical Research Council
Funding Amount
$384,686.00
Summary
Large-scale antimalarial drug screening projects have identified three different classes of compound that kill the malaria parasite at extremely low doses and which hold real promise as next-generation antimalarials. Genetic evidence, as well as preliminary data from our own lab, has led us to the hypothesis that all three compound classes exert their antimalarial effect by blocking a molecular ion pump on the parasite surface. The aim of this study is to test this.
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