Malaria drug resistance is associated with defective DNA mismatch repair

Model proposing the role of defective DNA mismatch repair in the development of multi-drug resistance by Plasmodium falciparum parasites. [Display omitted] ► Direct evidence of DNA mismatch repair activity in Plasmodium falciparum. ► Multi-drug resistant parasite strains possess defective DNA mismatch repair. ► Lack of PfMLH1 expression is the source of mismatch repair deficiency for W2 strain parasites. ► This study provides an exciting new hypothesis to explain the underlying mechanisms of P. falciparum drug resistance. Malarial parasites exhibit striking genetic plasticity, a hallmark of which is an ever-increasing rate of resistance to new drugs, especially in Southeast Asia where multi-drug resistance (MDR) threatens the last line of antimalarial drugs, the artesunate compounds. Previous studies quantified the accelerated resistance to multiple drugs (ARMD) phenomenon, but the underpinning mechanism(s) remains unknown. We utilize a forward genetic assay to investigate a new hypothesis that defective DNA mismatch repair (MMR) contributes to the development of MDR by Plasmodium falciparum parasites. We report that two ARMD parasites, W2 and Dd2, have defective MMR, as do the chloroquine-resistant parasites T9-94, 7C12, and 7G8. By contrast, the chloroquine-sensitive parasites HB3, D6 and 3D7 were MMR proficient. Interestingly, W2 was unable to repair substrates with a strand break located 3′ to the mismatch, which is attributable to a large observed decrease in PfMutLα content. These data imply that antimalarial drug resistance can result from defective MMR.