Correlation between Plasmodium yoelii nigeriensis susceptibility to artemisinin and alkylation of heme by the drug.

Evidence of artemisinin (ART) resistance in all of the Greater Mekong Region is currently of major concern. Understanding of the mechanisms of resistance developed by Plasmodium against artemisinin and its derivatives is urgently needed. We here demonstrated that ART was able to alkylate heme in mice infected by the ART-susceptible strain of Plasmodium yoelii nigeriensis, Y-control. After long-term drug pressure, the parasite strain (Y-ART3) was 5-fold less susceptible to ART than Y-control. In the blood of mice infected by Y-ART3, no heme-artemisinin adducts could be detected. After release of ART drug pressure, the parasite strain obtained (Y-REL) regained both drug susceptibility to ART and increased ability to produce covalent heme-artemisinin adducts. The correlation between parasite ART susceptibility and alkylation of heme by the drug confirms that heme or hemozoin metabolism is a key target for efficacy of ART as an antimalarial.