Deciphering the role of Plasmodium falciparum plasmepsin 2/3 amplifications in mutant pfcrt-driven piperaquine resistance

Emerging resistance to artemisinin-based combination therapies, the first-line treatment against Plasmodium falciparum (Pf) malaria, poses a major public health problem. Resistance to piperaquine (PPQ) and dihydro- artemisinin has now swept across Southeast Asia, with treatment failures as high as 87%. The increasing use of this combination in Africa adds to the threat of PPQ resistance spreading across this continent, where malaria exerts its heaviest toll. There is thus an urgent need to understand the mechanistic basis of PPQ resistance, alongside other studies focused on mutant PfKelch13-mediated artemisinin resistance. Recent studies have associated PPQ resistance with the amplification of plasmepsins 2/3 (pfpm 2/3) that encode two Pf hemoglobinases, as well as recently emerged mutations in the Pf chloroquine resistance transporter (PfCRT). These PfCRT mutations, which enable the efflux of PPQ away from its heme target in the parasite’s digestive vacuole, always occur on an amplified pfpm 2/3 genetic background, indicating an important role for these amplifications.

We will also generate translationally controlled TetR-DOZI- based conditional knockdowns of pfhdp in parasites with single or multicopy pfpm 2/3 and test whether these knockdowns modulate PPQ resistance and heme levels. These results will definitively assess the contribution of pfpm 2/3 amplifications to PPQ resistance. Mechanistic insights will also guide strategies to mitigate PPQ resistance by targeting the mediators of Hz formation, and inform the suitability of PfHDP as a novel drug target.

NIH project details

Drug Resistance

Mar 2021 — Feb 2024

$445,500

United States