News ID: 116004
Published: 0302 GMT April 19, 2015

Researchers make key malarial drug-resistance finding

Researchers make 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.

Laboratory studies showed that artemisinins were always active against the mature parasite stages that sequester in tissues, but clinicians were observing resistant infections from patients who were still in early stage of infections. In addition, previous genome wide association studies of P. falciparum identified genes associated with artemisinin resistance, but it was unknown how the genes worked. This Notre Dame-led 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, Science Daily wrote.

"We observed that levels of a lipid called phosphatidylinositol-3-phosphate (PI3P) were higher in artemisinin-resistant P. falciparum than artemisinin-sensitive strains," said Alassane Mbengue, a postdoctoral associate in biological sciences and co-first author on the study. "This lipid is produced by an enzyme called PfPI3K. We found that artemisinins block this kinase from producing PI3P lipids."

"We also discovered that the amount of the kinase present in the parasite is controlled by the gene PfKelch13," Mbengue said. "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. We 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."


Resource: Science Daily
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