Novel Artemisinin-based Combination Therapies For Children Exposed To High Transmission Of Multiple Plasmodium Species
Funder
National Health and Medical Research Council
Funding Amount
$1,378,408.00
Summary
We recently found that the WHO-recommended combination antimalarial therapy artemether-lumefantrine and the candidate regimen dihydroartemisinin-piperaquine were not fully effective for both falciparum and vivax malaria in young PNG children, a group at risk of complications and death. We plan to study two new combinations (artesunate-pyronaridine and artemisinin-naphthoquine) and hypothesise that at least one will prove superior and be used as first-line treatment in PNG and similar countries.
Functional Resolution Of PTEX, The Exporter Of Virulence Factors In Malaria Parasites.
Funder
National Health and Medical Research Council
Funding Amount
$625,212.00
Summary
Almost half a million people die each year of malaria and nearly half the world’s population are at risk. To eliminate malaria this century we will need new drugs and vaccine to fight the disease. One potential drug target are the molecular gateways called PTEX, that are used by parasites to export virulence proteins into their human host cells. This grant aims to understand how the PTEX molecular machines work so we can develop new drugs to block them and kill the parasites.
The Structural Resolution Of PTEX, The Translocon Of Virulence Proteins And Malaria Parasites.
Funder
National Health and Medical Research Council
Funding Amount
$561,028.00
Summary
The extraordinary virulence of malaria parasites is in part due to their ability to export hundreds of proteins into their red blood cell hosts that help them obtain nutrients and avoid the immune system. Recently we discovered the molecular machine that exports proteins into the host cell and we now wish to establish how it works so drugs can be tailored to block the machine and kill the parasites.
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.
Antimalarial Drugs In Pregnancy: Preclinical And Clinical Studies Of Conventional And Novel Agents
Funder
National Health and Medical Research Council
Funding Amount
$470,115.00
Summary
Women in malaria-endemic areas such as coastal PNG are at high risk of malaria in pregnancy. To prevent the substantially increased malaria-associated morbidity and mortality in mother and child, and because even asymptomatic infections can be deleterious, there has been a move to giving antimalarial drugs regularly during pregnancy regardless of the mother's clinical or parasitological status. In poor tropical countries, such treatment usually comprises safe and inexpensive agents such as chlor ....Women in malaria-endemic areas such as coastal PNG are at high risk of malaria in pregnancy. To prevent the substantially increased malaria-associated morbidity and mortality in mother and child, and because even asymptomatic infections can be deleterious, there has been a move to giving antimalarial drugs regularly during pregnancy regardless of the mother's clinical or parasitological status. In poor tropical countries, such treatment usually comprises safe and inexpensive agents such as chloroquine and Fansidar. There are two main issues with this approach. First, the efficacy of such conventional agents is waning and this increases the risk of break-through malaria. Second, there are few data on how the drugs are handled in pregnancy on which to base recommendations for treatment. We plan to collect information on the disposition and effectiveness of chloroquine and Fansidar in women with malaria in pregnancy in PNG that should allow a critical appraisal of the usefulness of current regimens in PNG and in other tropical countries where parasite resistance to these agents is emerging. Artemisinin combination therapy (ACT) in the form of a novel artemisinin drug and a longer-acting partner has been suggested as the most promising alternative therapy for malaria in pregnancy if conventional drugs fail. We plan to assess the safety of a leading ACT formulation, namely dihydroartemisinin and the chloroquine-like drug piperaquine (DHA-PQ), in animals before extending our studies to women with malaria in PNG. These latter studies will allow an evaluation of the safety and efficacy of DHA-PQ as novel therapy for malaria in pregnancy in PNG and other tropical countries.Read moreRead less
Improving The Therapeutic Use Of Anti-infective Agents: Application Of Pharmacometrics For Rational Dosing Regimen Design
Funder
National Health and Medical Research Council
Funding Amount
$313,390.00
Summary
There is no field of medicine in which the individualisation of medicines is more important than in infectious diseases – appropriate doses must be administered to maximise efficacy and to minimise side effects and the emergence of drug-resistance. This fellowship will use the emerging science of pharmacometrics to investigate factors contributing to the variability in response to anti-infective medications and to optimise dosing regimens for the best use of these drugs in clinical practice.
Development Of An In Vivo Pharmacokinetic-pharmacodynamic Model For Evaluation Of Antimalarial Drug Therapy Combinations
Funder
National Health and Medical Research Council
Funding Amount
$120,604.00
Summary
The World Health Organization currently estimates that there are 300-500 million cases of malaria annually, with 1.5-2.7 million deaths. These are staggering data, given that almost 20 antimalarial drugs are now in regular clinical use. Multi-drug resistance is present in most tropical countries where malaria is endemic and there has been a rapid escalation in cases of malaria in developed countries over recent decades (imported by travellers). Clearly, there is a need to ensure that current and ....The World Health Organization currently estimates that there are 300-500 million cases of malaria annually, with 1.5-2.7 million deaths. These are staggering data, given that almost 20 antimalarial drugs are now in regular clinical use. Multi-drug resistance is present in most tropical countries where malaria is endemic and there has been a rapid escalation in cases of malaria in developed countries over recent decades (imported by travellers). Clearly, there is a need to ensure that current and new treatment and prevention strategies are rational and effective. This project is based on the premise that improvements can be made in the in vitro testing process of antimalarial drugs. The experiments will be conducted using mice and a form of malaria that is specific to mice but closely resembles human malaria. In the first stage, the relationship between the amount of a new antimalarial drug (dihydroartemisinin) in the body and the effectiveness of the dose will be tested. These experiments will be repeated using conventional antimalarial drugs such as mefloquine. Information from these studies will subsequently be used to evaluate combinations of antimalarials. The results will be used as the basis of extensive, collaborative clinical studies in South-East Asia that are beyond the scope of this project. The methods used for this research will be important for future testing of new antimalarial drugs or combinations of drugs for the treatment and prophylaxis of malaria.Read moreRead less
Targeting Protein Synthesis In The Apicoplast And Cytoplasm Of Plasmodium
Funder
National Health and Medical Research Council
Funding Amount
$453,768.00
Summary
New antimalarial drugs are desperately needed. Protein synthesis in Plasmodium falciparum is a validated target for existing drugs and is a promising target for new drugs. This project brings together malaria biologists with chemists and computer scientists to explore this promising field. We will apply modern methods of drug target characterisation to find the most promising enzyme targets involved in protein synthesis and to identify inhibitors as leads for developing antimalarial therapies. A ....New antimalarial drugs are desperately needed. Protein synthesis in Plasmodium falciparum is a validated target for existing drugs and is a promising target for new drugs. This project brings together malaria biologists with chemists and computer scientists to explore this promising field. We will apply modern methods of drug target characterisation to find the most promising enzyme targets involved in protein synthesis and to identify inhibitors as leads for developing antimalarial therapies. Australian researchers involved in this project will provide expertise in bioinformatic prioritisation of Plasmodium drug targets from the aminoacyl tRNA synthetase family of enzymes. We will use structural modelling and docking experiments to identify promising antimalarial inhibitors, and will optimise assays to assess the effects of these inhibitors. We will also apply modern molecular biology tools to validate these enzymes as anti-malarial drug targets.Read moreRead less
The WHO estimates there were ~189 million clinical cases & 584,000 malaria-related deaths in 2013. This translates to ~1,600 child deaths daily. There is no licensed malaria vaccine & all available drugs are associated with resistant parasites. This enormous health issue is driving the search for new therapies. We address this issue by identifying new drug candidates for malaria prevention, with unique modes of action to treatment drugs in order to overcome issues of parasite drug resistance.