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Novel Fluorescent Probes Of Cellular Microenvironments To Study The Mechanism Of Action Of Endoperoxide Antimalarials
Funder
National Health and Medical Research Council
Funding Amount
$983,305.00
Summary
Malaria is responsible for the deaths of about two million children each year. As current drugs become increasingly useless due to the development of parasite resistance, there is an urgent need for new antimalarials. Artemisinin, an ancient Chinese drug that is extracted from wormwood, is now a front-line antimalarial, however its mechanism of action is not clear. Information about how artemisinin works is needed to help design cheap synthetic drugs that work in the same way.
The Mechanism Of Action Of New 5-nitroimidazole Drugs Which Are Effective Against Metronidazole-resistant Giardia
Funder
National Health and Medical Research Council
Funding Amount
$292,216.00
Summary
We have discovered new 5-nitroimidazole drugs which can overcome giardial resistance to metronidazole, the most prescribed 5-nitroimidazole drug to treat giardiasis. We will focus on defining mechanisms of action of these new 5-nitroimidazole drugs in the anaerobic gut protozoan parasite Giardia. Using biochemical techniques, we will determine whether our potent new drugs are activated more efficiently by the same mechanisms as metronidazole or by novel enzyme pathways in the parasite.
The Quinoline Antimalarials: Mechanisms Of Action And Resistance In Plasmodium Falciparum
Funder
National Health and Medical Research Council
Funding Amount
$316,650.00
Summary
Malaria is a debilitating parasitic disease that is responsible for the deaths of about two million children each year. As drugs, such as chloroquine, become increasingly useless due to the development of parasite resistance, there is an urgent need to understand the mode of action of these antimalarials so that replacement drugs can be designed. We propose to test the hypothesis that chloroquine acts by interfering with the detoxification of the by-products that are produced when the parasite f ....Malaria is a debilitating parasitic disease that is responsible for the deaths of about two million children each year. As drugs, such as chloroquine, become increasingly useless due to the development of parasite resistance, there is an urgent need to understand the mode of action of these antimalarials so that replacement drugs can be designed. We propose to test the hypothesis that chloroquine acts by interfering with the detoxification of the by-products that are produced when the parasite feeds on haemoglobin. We propose that the parasite develops resistance to chloroquine by excluding either the drug or the toxic by-products from the site of action. We further propose that proteins of the digestive vacuole of the parasite are involved in the development of resistance to chloroquine. We plan to identify and characterise these proteins and to use this information to design novel antimalarial drugs.Read moreRead less
Trafficking Of The Malaria Parasites Chloroquine Resistance Transporter
Funder
National Health and Medical Research Council
Funding Amount
$310,075.00
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 gain a better understanding of the protein underlying the resistance of the parasite to the drug chloroquine. This protein is located at an internal membrane within the parasite, but the elements which facilitate this localization are not known. This study will give valuable insights into the factors influencing the trafficking of parasite proteins to different membranes.
The PH Of The Malaria Parasite's Digestive Vacuole And Its Role In Antimalarial Drug Resistance
Funder
National Health and Medical Research Council
Funding Amount
$210,990.00
Summary
Malaria is an infectious disease that infects an estimated 300-500 million people and kills an estimated 1.5-2.7 million people annually. The microscopic parasite responsible for the disease is becoming increasingly resistant to most of the antimalarial drugs presently available. However the mechanisms by which it does so are very poorly understood. The malaria parasite invades the red blood cells of its victim. Once itside, it sets about consuming the contents of the cell, ingesting them and de ....Malaria is an infectious disease that infects an estimated 300-500 million people and kills an estimated 1.5-2.7 million people annually. The microscopic parasite responsible for the disease is becoming increasingly resistant to most of the antimalarial drugs presently available. However the mechanisms by which it does so are very poorly understood. The malaria parasite invades the red blood cells of its victim. Once itside, it sets about consuming the contents of the cell, ingesting them and depositing them in a small acidic compartment called the digestive vacuole. Many of the antimalarial drugs presently in use target this compartment and interfere with the processes going on inside it. There is evidence that resistance to antimalarial drugs arises as a result of changes in this compartment, though what these changes are, and how they occur remains a mystery. This work focuses on the mechanisms involved in controlling the acidity of the parasite's digestive vacuole. We have preliminary evidence that parasites showing different levels of antimalarial drug resistance have different levels of acidity in their vacuoles, and that this may be due to differences in the rate at which acid leaks from this compartment. The aim of this work is to obtain a detailed understanding on the mechanisms by which the acidity of the parasite's digestive vacuole is regulated and to gain some insight into whether and how these mechanisms might differ between drug-resistant and drug-sensitive parasites. By so doing, this work might be expected, in the long term, to provide a basis for the devolpment of new drugs with which to combat this deadly and increasingly threatening disease.Read moreRead less
Characterization Of The Chloroquine Resistance Transporter Of The Malaria Parasite
Funder
National Health and Medical Research Council
Funding Amount
$400,527.00
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 characterise the mechanism by which parasites have become resistant to the antimalarial drug chloroquine. Resistance is conferred by small changes in a single protein, but the underlying mechanism is not known. The results of this project will constitute a major advance in our understanding of the increasingly widespread phenomenon of antimalarial drug resistance.
Plasmodium Falciparum Neutral Aminopeptidases: Structure-function Analysis For The Discovery Of Anti-malarial Drugs.
Funder
National Health and Medical Research Council
Funding Amount
$634,027.00
Summary
Malaria is the world's most prevalent parasitic disease. Due to the spread of drug resistant parasites there is an urgent need to identify new anti-malaria targets and develop new drugs. We have shown that two enzymes, termed neutral aminopeptidases, are essential to the parasite's survival in the host. In this proposal we will obtain the structure of these enzymes and bring forth novel lead compounds that will form the basis of a new class of anti-malaria treatment.