Chloroquine Resistance in <i>Plasmodium falciparum</i> Malaria Parasites Conferred by <i>pfcrt</i> Mutations

TLDR

Chloroquine resistance in *Plasmodium falciparum* drives global malaria mortality and morbidity and has been linked to pfcrt point mutations, though causal evidence has been lacking. We demonstrate that pfcrt mutant haplotypes from Asia, Africa, and South America confer chloroquine resistance with verapamil reversibility and reduced drug accumulation, and that these mutations increase susceptibility to artemisinin and quinine while minimally affecting amodiaquine, suggesting these antimalarials merit further study.

Abstract

Plasmodium falciparum chloroquine resistance is a major cause of worldwide increases in malaria mortality and morbidity. Recent laboratory and clinical studies have associated chloroquine resistance with point mutations in the gene pfcrt . However, direct proof of a causal relationship has remained elusive and most models have posited a multigenic basis of resistance. Here, we provide conclusive evidence that mutant haplotypes of the pfcrt gene product of Asian, African, or South American origin confer chloroquine resistance with characteristic verapamil reversibility and reduced chloroquine accumulation. pfcrt mutations increased susceptibility to artemisinin and quinine and minimally affected amodiaquine activity; hence, these antimalarials warrant further investigation as agents to control chloroquine-resistant falciparum malaria.