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.
Recognition Of Macromolecular Complexes By Cell Surface Receptors: A Novel Mechanism Of Lipid And Drug Absorption
Funder
National Health and Medical Research Council
Funding Amount
$398,156.00
Summary
A clear understanding of the mechanisms by which orally ingested materials are absorbed from the gastrointestinal tract is critical in areas such as nutrition, drug development and toxicology. The current project aims to evaluate the role of specific receptor types in the intestine in the absorption of both dietary lipids and drug molecules, with a view to providing a means to better regulate lipid absorption and to more effectively facilitate the design of improved drug delivery systems.
New drugs for cancer therapy that overcome resistance to standard chemotherapeutics and stop the spread of cancer are essential to develop. My preliminary studies discovered a strategy to increase the activity and delivery of our novel compounds to enhance the killing of cancer cells. I will design innovative agents in an effort to provide more effective therapeutics with fewer side effects to reduce the pain of cancer patients undertaking chemotherapy who are in the battle of their lives.
Circuit Breaker: Investigating The Regulatory Circuits Controlling Expression Of Drug Efflux Pumps In The Nosocomial Pathogen Acinetobacter Baumannii
Funder
National Health and Medical Research Council
Funding Amount
$515,244.00
Summary
Hospital-acquired infections caused by drug resistant pathogenic bacteria cost billions of dollars and increase patient pain and morbidity. This research will study the genes controlling multidrug efflux pumps in a major hospital-acquired bacterial pathogen, Acinetobacter baumannii. These efflux pumps make the bacteria resistant to antimicrobials by pumping them out of the cell. The results will allow us to better track drug resistant strains and will inform treatment options.
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
Predicting Drug-drug Interactions Due To Tyrosine Kinase Inhibitors: Inhibition Of Drug Metabolising Enzymes And Transporters
Funder
National Health and Medical Research Council
Funding Amount
$535,495.00
Summary
Tyrosine kinase inhibitors (TKIs) are a new class of anticancer agents. Cancer patients typically receive multiple drugs, for the treatment of cancer and other diseases, increasing the probability of interactions between coadministered drugs. Despite the widespread use of TKIs, their potential to cause drug interactions is poorly understood. Using novel in vitro approaches, this project will identify drug interactions precipitated by TKIs thereby improving drug efficacy and patient safety.
Interaction Of New Kinase Inhibitor Drugs With Multi-drug Resistance (MDR) Transporter Proteins.
Funder
National Health and Medical Research Council
Funding Amount
$411,000.00
Summary
Multidrug transporter proteins are remarkable molecular pumps that expel a wide variety of drugs and toxins from cells. They are located at strategic sites where they eliminate harmful substances from the body or prevent them being absorbed from our diet in the first place. Multidrug transporters are also found at natural barriers within the body where they protect vulnerable tissue compartments, including the brain, cerebrospinal fluid, testes and, in preganant women, the foetus. Nevertheless, ....Multidrug transporter proteins are remarkable molecular pumps that expel a wide variety of drugs and toxins from cells. They are located at strategic sites where they eliminate harmful substances from the body or prevent them being absorbed from our diet in the first place. Multidrug transporters are also found at natural barriers within the body where they protect vulnerable tissue compartments, including the brain, cerebrospinal fluid, testes and, in preganant women, the foetus. Nevertheless, multidrug transporters sometimes interfere with drug therapy. They can prevent efficient absorption of drugs, increase the rate of drug elimination from the body, or prevent drug access to some tissues . Moreover, the activity of the transporters is quite variable, both between patients and within the same patient over time. This makes it difficult to provide optimal drug doses, particularly when treating cancer, where the drugs must be given at the maximum tolerated dose. The presence of drug transporter proteins in tumour cells can prevent entry of anticancer drugs, rendering them resistant to treatment. This is the main cause of failure in chemotherapy. This project will investigate a class of very promising new anticancer drugs, kinase inhibitors, to determine whether they are pumped by multidrug transporters, whether they alter the amounts of drug transporters in cells, and whether they alter transporter activity. We will also determine the consequences that follow from this for drug therapy. This information will help clinicians to rationally optimise therapy with the new drugs, to identify in advance both favourable (synergistic) and unfavourable (harmful) drug interactions in combination chemotherapy, to optimise drug doses and to minimise toxic side effects. The information will also add to our general understanding of drug absorption and elimination, and to the basic science of the remarkable multidrug transporter proteins.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.
An Ace Up Their Sleeve: Characterisation Of A Novel Family Of Drug Efflux Systems Represented By The Acinetobacter AceI Exporter
Funder
National Health and Medical Research Council
Funding Amount
$400,286.00
Summary
Chlorhexidine is widely used as an antiseptic in products such as skin washes, soaps, mouthwashes, disinfectants and preservatives. We have recently discovered a novel bacterial protein which pumps chlorhexidine out of bacterial cells to make them resistant to this antiseptic agent. This proposal aims to understand this resistance mechanism and to find inhibitors which could be applied in clinical settings to augment the activity of chlorhexidine.