Chloroquine (CQ) used to be considered the gold standard in the treatment of malaria caused by the parasite Plasmodium falciparum. However, several strains of P. falciparum are emerging as drug resistant and compromising the current drug treatment. Researchers at the University of São Paulo, Brazil, have been studying the Plasmodium life cycle to discover possible new drug targets that can disrupt the resurgence of this health threat.

A team led by Celia R. S. Garcia discovered the first G-protein–coupled receptor in P. falciparum that has the dual function of sensing the environmental change and drug-induced stress survival. P. falciparum chloroquine resistance transporter (or PfCRT) is central to understanding the parasite’s mechanism of antimalarial resistance. Garcia, in collaboration with David Fidock at Columbia University among others, reported recently that this drug/metabolite transporter localizes to the digestive vacuole (DV) membrane of intra-erythrocytic asexual blood stage parasites.1

“Mutant PfCRT is the key determinant of resistance to the former first-line drug chloroquine (CQ), a 4-aminoquinoline that accumulates to micromolar or higher concentrations in the acidic DV wherein its diprotonated form binds to reactive heme and inhibits its detoxification,” Garcia said.

To better understand how PfCRT works, the team used a gene-edited mutation in the PfCRT of the parasite. Results indicated that the mutation makes the parasite more vulnerable, prevents it from metabolizing its energy sources, and controls the parasite’s susceptibility to several anti-malarial drugs.

“Our findings support the hypothesis that PfCRT is involved in regulating parasite access to globin-derived peptides that are necessary for de novo protein synthesis and balancing ionic homeostasis in the DV that is a key factor in maintaining the catalytic efficiency of Hb peptidases,” Garcia wrote. “Given the central role of PfCRT both in parasite development and in resistance to heme-binding antimalarials, there is a pressing need to elucidate its biological functions in the context of parasite physiology and to leverage these insights into identifying novel approaches to combat P. falciparum multidrug resistance.”

Reference

1Lee AH et al. (2018). Evidence for regulation of hemoglobin metabolism and intracellular ionic flux by the Plasmodium falciparum chloroquine resistance transporter. Scientific Reports 8, 13578.

Mary Spiro

Mary Spiro is ASCB's Science Writer and Social Media Manager.