Development of a novel mouse model of artemisinin resistant malaria to screen and prioritize antimalaria drugs effective against artemisinin-resistant parasites

A major obstacle to malaria elimination is the ability of malaria parasites to develop resistance to drug treatment. Worryingly, malaria parasites (P. falciparum) resistant to artemisinin have emerged and spread in Southeast Asia. Artemisinin is the basis of the current first-line treatment for malaria, therefore, new treatments against artemisinin-resistant parasites are urgently needed. Testing antimalarial drugs in humans is costly and timeconsuming. Humanised mouse models provide an optimal alternative to study antimalarial drug effects against human malaria parasites. Drugs would be first tested in humanised mice, and only the ones showing promising antimalarial activity would progress to be tested in humans. In this project, we will use a humanised mouse model, where mice have been engrafted with human red blood cells. Humanised mice will be infected with P. falciparum malaria parasites resistant to artemisinin, to produce an artemisinin-resistant mouse model. Mice from the artemisinin-resistant mouse model will be treated with a single-dose of artesunate (an artemisinin derivative). We will test how well artesunate works by estimating pharmacokinetic and pharmacodynamics (PKPD) parameters, which measure how fast the drug is absorbed into blood circulation and excreted, and how quickly the number of parasites declined after treatment. We aim to determine if our artemisinin-resistant mouse model can predict outcomes in humans. To test this, we will compare artesunate PK-PD parameters in the artemisinin-resistant mouse model with parameter values derived from a human malaria challenge study recently conducted by our group, in which volunteers were infected with artemisinin-resistant parasites and treated with single-dose artesunate. Once we confirm the artemisinin-resistant mouse model is able to predict outcomes in humans, this model can be used to screen and select the antimalarial drugs and drug combinations most effective against artemisininresistant parasites. The most potent drugs can then progress to clinical development in human malaria challenge studies.

Drug Resistance
Drug-based Strategies
Product Development

Nov 2018 — Oct 2023

$15,000

Australia

Australian Centre for Research Excellence in Malaria Elimination (ACREME)