Molecular markers of Plasmodium resistance to antimalarials

Abstract

Investigations into the molecular basis of Plasmodium parasite resistance to antimalarial drugs have made strong progress in defining key determinants. Mutations in the digestive vacuole transmembrane proteins P. falciparum chloroquine resistance transporter (PfCRT) and P. falciparum multidrug resistance protein 1 (PfMDR1) are important drivers of parasite resistance to several quinoline-based drugs including chloroquine, amodiaquine, and to a lesser extent quinine. Amplification of pfmdr1 can also mediate resistance to mefloquine and impact lumefantrine efficacy. Parasite resistance to antifolates has been mapped to point mutations in the target enzymes dihydrofolate reductase and dihydropteroate synthase, and mutations in cytochrome b have been found to ablate atovaquone efficacy. Antibiotic resistance has been associated with mutations that preclude drug inhibition of protein translation in the parasite apicoplast. The study of resistance to artemisinin derivatives and several partner drugs used in artemisinin-based combination therapies is an area of active research that has yet to define clearly how in vitro resistance can translate into predictions of treatment failures. Research in this area is important not only for its ability to generate molecular markers of treatment failure but also for the insights it can provide into drug mode of action and the development of chemical and pharmacological strategies to overcome resistance mechanisms.