Inactivation of Plasmepsins 2 and 3 Sensitizes Plasmodium falciparum to the Antimalarial Drug Piperaquine

Dihydroartemisinin-piperaquine (DHA-PPQ), the current frontline artemisinin combination therapy used to treat 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 sp...

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Bibliographic Details
Published in:Antimicrobial agents and chemotherapy 2018-04, Vol.62 (4)
Main Authors: Mukherjee, Angana, Gagnon, Dominic, Wirth, Dyann F, Richard, Dave
Format: Article
Language:English
Subjects:
Antimalarials
Antimalarials - pharmacology
Aspartic Acid Endopeptidases
Aspartic Acid Endopeptidases - genetics
Aspartic Acid Endopeptidases - metabolism
Drug Resistance - genetics
Mechanisms of Resistance
Plasmodium falciparum
Plasmodium falciparum - drug effects
Plasmodium falciparum - genetics
Plasmodium falciparum - metabolism
Protozoan Proteins
Protozoan Proteins - genetics
Protozoan Proteins - metabolism
Quinolines
Quinolines - pharmacology
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Summary:Dihydroartemisinin-piperaquine (DHA-PPQ), the current frontline artemisinin combination therapy used to treat 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 the genes encoding 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 show here that inactivating the genes encoding plasmepsin 2 or 3 individually in reference strain 3D7 results in hypersusceptibility to PPQ. Interestingly, no significant differences in the susceptibility to other antimalarials were observed, which suggests specific roles of plasmepsins 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 and independent of Kelch13 mutations conferring artemisinin resistance.
ISSN:0066-4804
1098-6596
DOI:10.1128/AAC.02309-17