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.
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.
Application Of New Chemistry Approaches For Antimalarial Drug Discovery
Funder
National Health and Medical Research Council
Funding Amount
$74,263.00
Summary
Malaria kills approximately one million people annually. Currently there no vaccine and many of the available drugs are becoming less effective due the resistance of this highly adaptable parasite. My aim is to develop new chemical classes of drugs that inhibit different targets in the malaria parasite to the currently available drugs. In addition to this I aim to improve the present systems for assessing antimalarial drug effects using new chemical approaches and live parasite assays.
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.
Trafficking Of The Major Virulence Protein To The Host Cell Surface In Malaria Parasite-infected Erythrocytes
Funder
National Health and Medical Research Council
Funding Amount
$658,164.00
Summary
The malaria parasite infects human red blood cells and causes them to stick to blood vessels in the brain, inducing coma. This causes the deaths of ~2 million children each year. We will use cell biology techniques to manipulate malaria parasites to unravel the details of the molecular ticketing system that the parasite uses to get its adhesive proteins onto the red blood cell surface. The ability to interfere with this process would greatly decrease the impact of this major human pathogen.
Phenotypic Characterization Of Chloroquine Resistance In Plasmodia
Funder
National Health and Medical Research Council
Funding Amount
$585,473.00
Summary
In the Asia-Pacific region, vivax malaria is becoming the dominant species of infection. The emergence and spread of chloroquine resistant strains of P. vivax threatens malaria control and elimination efforts. This project aims to elucidate fundamental aspects of chloroquine resistance in non-falciparum malaria and identify novel therapeutic options. We will develop novel tests that will help national malaria control programs to monitor declining activity of standard anti-malarial drugs.
Developing Synergisers Of The Antimalarial Drug, Chloroquine, For The Treatment Of Chloroquine-resistant P. Falciparum.
Funder
National Health and Medical Research Council
Funding Amount
$243,000.00
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 and the molecular basis of resistance to existing antimalarials and to design affordable treatments that can replace chloroquine. It is known that some compounds, that have only poor antimalarial activity themselve ....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 and the molecular basis of resistance to existing antimalarials and to design affordable treatments that can replace chloroquine. It is known that some compounds, that have only poor antimalarial activity themselves, can synergise the action of chloroquine. This may involve the inhibition of the activity of proteins that directly or indirectly extrude chloroquine from its site of action in the parasite's digestive apparatus. Unfortunately, thechloroquine synergisers examined to date have been too toxic to be useful in vivo. In preliminary studies we have identified some compounds that would be suitable for use in malaria patients, including a widely used antimalarial drug, primaquine, that can synergise the activity of chloroquine against chloroquine-resistant parasites. We will attempt to understand the molecular basis of this interaction. This will allow us to define optimal combinations of chloroquine and a resistance-reversing quinoline for use treating malaria. This could extend the clinical life of this important antimalarial drug. The information obtained may also help to design novel antimalarial drugs.Read moreRead less
Combating Giardiasis By Investigating New Potent Compound Series As Leads For Improved Treatment Options
Funder
National Health and Medical Research Council
Funding Amount
$776,028.00
Summary
Giardia parasites infect ~1 billion people globally and are responsible for significant morbidity and disadvantage. There is no licensed vaccine and current treatment options are inadequate, resulting in poor compliance, treatment failures, rapid re-infection and drug resistance. New therapies are needed to combat this parasite and improve the health of millions world-wide. We will address this issue by investigating new drug candidates for the treatment of Giardia infections.
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.
In 2013 there were ~200 million clinical cases of malaria, causing ~600,000 deaths. All antimalarial drugs are now associated with malaria parasite resistance. Thus, new therapies are urgently needed, including new drugs to prevent this disease. We have made the exciting discovery that an existing antimalarial drug can kill malaria parasites in a unique, previously unknown, manner. Here, we will investigate how this occurs and develop new drug candidates for malaria prevention.