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Background The rise in  Plasmodium falciparum  resistance to dihydroartemisinin–piperaquine (DHA–PPQ) treatment has been documented in the Greater Mekong Subregion with associations with mutations in the  P. falciparum  chloroquine resistance transporter ( pfcrt ) and plasmepsin 2 ( pfpm2 ) genes. However, it is unclear whether other genes also play a role with PPQ resistance, such as the E415G mutation in the exonuclease ( pfexo ) gene. The aim of this study was to investigate the role of this mutation in PPQ resistance by generating transgenic parasites expressing the  pfexo -E415G mutant allele. Methods Transgenic parasite clones carrying the E415G mutation in  PfEXO of the B5 isolate were derived by CRISPR-Cas9 gene editing and verified using PCR and gene sequencing. Polymorphisms of  pfkelch-13 ,  pfcrt , and  pfexo  were examined by PCR while the copy number variations of  pfpm2  were examined by both relative quantitative real-time PCR and the duplication breakpoint assay. Drug sensitivity against a panel of antimalarials, the ring-stage survival assay (RSA), the PPQ survival assay (PSA), and bimodal dose-response curves were used to evaluate antimalarial susceptibility. Results The transgenic line, B5- rexo -E415G-B8, was successfully generated. The PPQ-IC 90 , %PPQ survival, and the bimodal dose-response clearly showed that E415G mutation in PfEXO of B5 isolate remained fully susceptible to PPQ. Furthermore, growth assays demonstrated that the engineered parasites grew slightly faster than the unmodified parental isolates whereas  P. falciparum  isolates harbouring  pfkelch-13 ,  pfcrt , and  pfexo  mutations with multiple copies of  pfpm2  grew much more slowly. Conclusions Insertion of the E415G mutation in PfEXO did not lead to increased PPQ-IC 90  and %PPQ survival, suggesting that this mutation alone may not be associated with PPQ resistance, but could still be an important marker if used in conjunction with other markers for monitoring PPQ-resistant parasites. The results also highlight the importance of monitoring and evaluating suspected genetic mutations with regard to parasite fitness and resistance.

A single point mutation in the Plasmodium falciparum 3′–5′ exonuclease does not alter piperaquine susceptibility