Researchers identify molecular mechanism responsible for making malaria parasites drug-resistant

A team of researchers has made key malarial drug-resistance finding.

Artemisinins are powerful drugs that have the most rapid action of all current drugs against Plasmodium falciparum, the parasite species that causes the most dangerous form of malaria. Artemisinin combination therapies (ACTs) are now standard treatment worldwide for P. falciparum malaria. Unfortunately, resistance to artemisinin has been detected in five countries across Southeast Asia. Along the Cambodia-Thailand border, P falciparum is now resistant to most available antimalarial drugs. Artemisinin resistance poses a serious global threat to malaria control and elimination.

Researcher Kasturi Haldar said that there are two phases of blood stage malaria infection. In the first phase, the "ring" parasite stage circulates in the bloodstream, and in the second phase, the "mature" parasite stage sequesters in the tissues of the body, adding that artemisinins are highly effective in treating malaria quickly because they target the first ring stage. When patients take the medication, their fevers reduce quickly, and the parasite is eliminated rapidly.

This University Of Notre Dame's study identified both the target of artemisinins in the clinically affected ring stages and how a gene named PfKelch13, a dominant marker used to track the parasite's resistance, causes artemisinin resistance.

Co-first author Alassane Mbengue said that they observed that levels of a lipid called phosphatidylinositol-3-phosphate (PI3P) were higher in artemisinin-resistant P. falciparum than artemisinin-sensitive strains and this lipid is produced by an enzyme called PfPI3K. They found that artemisinins block this kinase from producing PI3P lipids. Mbengue added that they also discovered that the amount of the kinase present in the parasite is controlled by the gene PfKelch13. Mutation in the gene increases the kinase levels, which in turn increases PI3P lipid levels. The higher the level of PI3P lipids present in the parasite, the greater the level of artemisinin resistance.

They also studied the lipid levels in parasites without the gene mutation and observed that when PI3P lipid levels were increased artificially, the parasites still became proportionately resistant.

The study appears online in Nature.