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
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.
Coenzyme A Synthesis In The Human Malaria Parasite, Plasmodium Falciparum
Funder
National Health and Medical Research Council
Funding Amount
$428,250.00
Summary
Malaria is responsible for hundreds of millions of cases and an estimated 1.5-2.7 million deaths each year. The disease is caused by a microscopic parasite which is becoming increasingly resistant to antimalarial drugs. There is a very real possibility that there will soon be parts of the world in which malaria is an untreatable disease, and there is an urgent need to identify new drug targets. This work focuses on a particular biochemical pathway in the human malaria parasite, Plasmodium falcip ....Malaria is responsible for hundreds of millions of cases and an estimated 1.5-2.7 million deaths each year. The disease is caused by a microscopic parasite which is becoming increasingly resistant to antimalarial drugs. There is a very real possibility that there will soon be parts of the world in which malaria is an untreatable disease, and there is an urgent need to identify new drug targets. This work focuses on a particular biochemical pathway in the human malaria parasite, Plasmodium falciparum. The pathway mediates the conversion of the nutrient, vitamin B5, into a molecule called Coenzyme A. It plays an essential role in the intraerythrocytic parasite and our preliminary data indicate that components of this pathway hold significant potential as antimalarial drug targets. In this project we will use a range of biochemical and molecular biology approaches to characterise in detail the components of this pathway in the parasite and to explore the possibility that compounds that inhibit this pathway may be of value as much-needed new antimalarial agents.Read moreRead less
Ion Transport In The Human Malaria Parasite, Plasmodium Falciparum
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
Malaria is responsible for hundreds of millions of cases and an estimated 1.5-2.7 million deaths each year. The disease is caused by a microscopic parasite which is becoming increasingly resistant to antimalarial drugs. There is a very real possibility that there will soon be parts of the world in which malaria is an untreatable disease, and there is an urgent need to identify new drug targets. However, despite the significance of the malaria parasite for world health, the basic physiology of th ....Malaria is responsible for hundreds of millions of cases and an estimated 1.5-2.7 million deaths each year. The disease is caused by a microscopic parasite which is becoming increasingly resistant to antimalarial drugs. There is a very real possibility that there will soon be parts of the world in which malaria is an untreatable disease, and there is an urgent need to identify new drug targets. However, despite the significance of the malaria parasite for world health, the basic physiology of this organism is poorly understood. This project focuses on the mechanisms involved in ion balance in the parasite. Ion balance is a basic 'housekeeping' function in all cells, and disruption of the mechanisms involved will inevitably impair cell function. The work proposed here will lead to an understanding of ion balance in the intracellular parasite and provide insight into whether the mechanisms involved may be suitable antimalarial drug targets.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 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
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.