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Piperaquine Resistance

Three graphs and a table show data related to Plasmodium falciparum resistance to piperaquine. Graph A displays PSA fold change. Graph B displays AUC. Graph C displays limited point IC50. The bottom graph shows the percentage of total samples with different pfCRT mutations and amplifications by year. The table shows percentages of multicopy pm2/3 samples and documented PPQ-R mutations by country and globally.

Piperaquine (PPQ) remains a highly effective ACT partner drug in Africa, despite the rapid spread of PPQ resistance in Southeast Asia. Resistance to this partner drug has been found to be mediated by mutations in pfcrt as well as copy number amplification of plasmepsin II/III. The KH004 parent of the KH004xMal31 genetic cross contains both a PPQ resistance conferring pfcrt genotype as well as 4 copies of plasmepsin II/III. By using progeny of this cross, we were able to identify the individual contributions of these two loci as well as the epistatic interactions between them. As resistance to the DHA+PPQ combination therapy continues to expand, we will use future crosses to continue to understand resistance to PPQ and the underlying genetic architecture required for resistance to emerge in Africa.

References

Kane J, Li X, Kumar S, Button-Simons KA, Vendrely Brenneman KM, Dahlhoff H, Sievert MAC, Checkley LA, Shoue DA, Singh PP, Abatiyow BA, Haile MT, Nair S, Reyes A, Tripura R, Peto TJ, Lek D, Mukherjee A,Kappe SHI, Dhorda M, Nkhoma SC, Cheeseman IH,Vaughan AM, Anderson TJC, Ferdig MT.2024. A Plasmodium falciparum genetic cross reveals the contributions of pfcrt and plasmepsin II/III to piperaquine drug resistance.mBio15:e00805-24. https://doi.org/10.1128/mbio.00805-24