Inactivation of Plasmepsin 2 and 3 sensitizes Plasmodium falciparum to the antimalarial drug piperaquine [PublishAheadOfPrint]

Dihydroartemisinin-piperaquine (DHA-PPQ), the current frontline artemisinin combination therapy used to treat Plasmodium falciparum malaria in multiple Southeast Asian countries is now increasingly failing in Cambodia where artemisinin resistance is nearly fixed which suggests that PPQ resistance has emerged and is spreading rapidly in the Greater Mekong Subregion. Recent reports have shown that amplification of Plasmepsins 2 and 3 is a molecular marker of PPQ resistance however whether these enzymes play a role in the mechanism of resistance is currently unknown. We here show that inactivating Plasmepsin-2 or Plasmepsin-3 individually in the 3D7 P. falciparum reference strain results in hyper-susceptibility to PPQ. Interestingly, no significant differences in the susceptibility to other antimalarials were observed which suggests specific roles of Plasmepsin 2 and 3 in PPQ susceptibility. The piperaquine hyper-sensitivity of the Plasmepsin 2 and 3 inactivated lines provides direct evidence that these enzymes modulate parasite susceptibility to PPQ in the context of a single copy of PfMDR1 and independent of Kelch13 mutations conferring ART resistance.

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