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.
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
Cytosolic And Organellar TRNA Synthetases In Plasmodium Falciparum
Funder
National Health and Medical Research Council
Funding Amount
$424,262.00
Summary
Malaria is a major worldwide infectious disease. The disease kills around 2 million people every year, and current drugs are increasingly failing due to parasite drug resistance, creating an urgent demand for new drugs, that inhibit different targets. I will study a new class of parasite drug targets, the tRNA synthetase enzymes to find novel inhibitors. Compounds blocking these enzymes may lead to new drugs to combat malaria.
New Antimalarial Drug Leads Targeting Multiple Species And Life Cycle Stages
Funder
National Health and Medical Research Council
Funding Amount
$818,477.00
Summary
Malaria causes ~200 million clinical cases and >430,000 deaths annually. Prevention and treatment relies on drugs, however malaria parasite drug resistance is an enormous problem. To address this issue, and aim towards eliminating malaria, we need to develop new drugs. This project addresses this important health need by investigating the ability of new chemical compounds, developed at CSIRO, to kill human-infecting malaria parasites during different parts of their complicated lifecycles.
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.
Retargeting The Antibiotic Azithromycin As An Antimalarial With Dual Modality.
Funder
National Health and Medical Research Council
Funding Amount
$773,613.00
Summary
Malaria parasites resistant to first-line treatments continue to spread in South East Asia. New drugs need to be developed urgently to ensure alternative treatment strategies are available. We will retarget the safe and widely used antibiotic azithromycin as an antimalarial with dual modalities against parasite invasion and growth inside the host red blood cell. This strategy has significant potential to increase drug efficacy while reducing the chances for the development of resistance.
Centre For Research Excellence In Malaria Elimination
Funder
National Health and Medical Research Council
Funding Amount
$2,470,291.00
Summary
The CRE will work to accelerate progress towards malaria elimination in our region, through Surveillance, to develop better ways to monitor malaria transmission and discover who is infected, and to track movement of malaria parasites and spread of drug resistance. Diagnosis, to develop and test new, more sensitive ways of detecting malaria. Treatment, to fast track development of new antimalarials, and improve access to ensure all infected people get highly effective drugs.
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