Plasmodium falciparum proteins associated with resistance

Plasmodium falciparum proteins associated with resistance collectively refer to a diverse group of molecular targets within the parasite that mediate resistance to multiple classes of antimalarial drugs. Chief among these are transporter proteins such as the ATP-binding cassette (ABC) transporters (PfMDR1, PfCRT, PfMRP1, and PfMRP2) which control the efflux and influx of various drugs, modulating their concentration within parasite compartments. Enzyme targets such as dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) are involved in folate metabolism and serve as central mediators of resistance to antifolates like pyrimethamine and sulfadoxine. Kelch13, a protein with a kelch propeller domain, is central to artemisinin resistance and intracellular trafficking. Mutations or copy number variations in these proteins account for most resistance phenotypes, and these molecules serve as epidemiological biomarkers and direct therapeutic targets. The complexity and redundancy of these resistance mechanisms present significant challenges for malaria control and treatment, as they enable rapid adaptation to new therapeutic pressures and cross-resistance, elevating the risk of large-scale drug failure[1][2][3][5][7][8].

Other names

Plasmodium falciparum multidrug resistance proteinsP. falciparum drug resistance proteinsPfMDR1 (Plasmodium falciparum multidrug resistance protein 1)PfCRT (Plasmodium falciparum chloroquine resistance transporter)PfK13 (Plasmodium falciparum Kelch 13)PfMRP1PfMRP2 (Multidrug resistance–associated proteins 1 and 2)Pfdhfr (dihydrofolate reductase)Pfdhps (dihydropteroate synthase)

Inhibition of drug transporters, leading to increased drug accumulation in the parasite (ABC transporter inhibitors and drugs affected by transporter mutations) Blockage of folate biosynthesis enzymes (antifolates pyrimethamine, sulfadoxine acting on Pfdhfr, Pfdhps) Heme detoxification inhibition (affected by PfCRT) Modulation of hemoglobin endocytosis and activation of pro-drugs (Kelch13, affects artemisinin response)