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infecting a red blood cell
Image courtesy of St. Jude
Children’s Research Hospital
Researchers say they have identified a molecular mechanism responsible for making malaria parasites resistant to artemisinins, the leading class of antimalarial drugs.
The team found that a kinase, Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K), and its lipid product, phosphatidylinositol-3-phosphate (PI3P), play key roles in artemisinin resistance.
So targeting PfPI3K or PI3P could potentially treat resistant Plasmodium falciparum malaria.
Alassane Mbengue, PhD, of the University of Notre Dame in Indiana, and his colleagues described this research in a letter to Nature.
“We observed that levels of [PI3P] were higher in artemisinin-resistant P falciparum than artemisinin-sensitive strains,” Dr Mbengue said. “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.”
“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.”
Specifically, the researchers found that increased PfPI3K was associated with the C580Y mutation in PfKelch13. The mutation reduced polyubiquitination of PfPI3K and its binding to PfKelch13, which limited proteolysis of PfPI3K and led to increased levels of both PfPI3K and PI3P.
The team found that PI3P levels were predictive of artemisinin resistance in clinical and engineered parasites. And although increases in PI3P levels induced artemisinin resistance in the absence of PfKelch13 mutations, PI3P levels were still responsive to regulation by PfKelch13.
Dr Mbengue and his colleagues said the next step for this research is to identify drugs that can kill P falciparum by preventing PfPI3K from making PI3P or disrupting the production of the kinase itself. 
infecting a red blood cell
Image courtesy of St. Jude
Children’s Research Hospital
Researchers say they have identified a molecular mechanism responsible for making malaria parasites resistant to artemisinins, the leading class of antimalarial drugs.
The team found that a kinase, Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K), and its lipid product, phosphatidylinositol-3-phosphate (PI3P), play key roles in artemisinin resistance.
So targeting PfPI3K or PI3P could potentially treat resistant Plasmodium falciparum malaria.
Alassane Mbengue, PhD, of the University of Notre Dame in Indiana, and his colleagues described this research in a letter to Nature.
“We observed that levels of [PI3P] were higher in artemisinin-resistant P falciparum than artemisinin-sensitive strains,” Dr Mbengue said. “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.”
“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.”
Specifically, the researchers found that increased PfPI3K was associated with the C580Y mutation in PfKelch13. The mutation reduced polyubiquitination of PfPI3K and its binding to PfKelch13, which limited proteolysis of PfPI3K and led to increased levels of both PfPI3K and PI3P.
The team found that PI3P levels were predictive of artemisinin resistance in clinical and engineered parasites. And although increases in PI3P levels induced artemisinin resistance in the absence of PfKelch13 mutations, PI3P levels were still responsive to regulation by PfKelch13.
Dr Mbengue and his colleagues said the next step for this research is to identify drugs that can kill P falciparum by preventing PfPI3K from making PI3P or disrupting the production of the kinase itself.
infecting a red blood cell
Image courtesy of St. Jude
Children’s Research Hospital
Researchers say they have identified a molecular mechanism responsible for making malaria parasites resistant to artemisinins, the leading class of antimalarial drugs.
The team found that a kinase, Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K), and its lipid product, phosphatidylinositol-3-phosphate (PI3P), play key roles in artemisinin resistance.
So targeting PfPI3K or PI3P could potentially treat resistant Plasmodium falciparum malaria.
Alassane Mbengue, PhD, of the University of Notre Dame in Indiana, and his colleagues described this research in a letter to Nature.
“We observed that levels of [PI3P] were higher in artemisinin-resistant P falciparum than artemisinin-sensitive strains,” Dr Mbengue said. “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.”
“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.”
Specifically, the researchers found that increased PfPI3K was associated with the C580Y mutation in PfKelch13. The mutation reduced polyubiquitination of PfPI3K and its binding to PfKelch13, which limited proteolysis of PfPI3K and led to increased levels of both PfPI3K and PI3P.
The team found that PI3P levels were predictive of artemisinin resistance in clinical and engineered parasites. And although increases in PI3P levels induced artemisinin resistance in the absence of PfKelch13 mutations, PI3P levels were still responsive to regulation by PfKelch13.
Dr Mbengue and his colleagues said the next step for this research is to identify drugs that can kill P falciparum by preventing PfPI3K from making PI3P or disrupting the production of the kinase itself.