The natural function of the malaria parasite’s chloroquine resistance transporter

Sarah H. Shafik, Simon A. Cobbold, Kawthar Barkat, Sashika N. Richards, Nicole S. Lancaster, Manuel Llinás, Simon J. Hogg, Robert L. Summers, Malcolm J. McConville and Rowena E. Martin ()
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Sarah H. Shafik: The Australian National University
Simon A. Cobbold: University of Melbourne
Kawthar Barkat: The Australian National University
Sashika N. Richards: The Australian National University
Nicole S. Lancaster: The Australian National University
Manuel Llinás: The Pennsylvania State University
Simon J. Hogg: The Australian National University
Robert L. Summers: The Australian National University
Malcolm J. McConville: University of Melbourne
Rowena E. Martin: The Australian National University

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract The Plasmodium falciparum chloroquine resistance transporter (PfCRT) is a key contributor to multidrug resistance and is also essential for the survival of the malaria parasite, yet its natural function remains unresolved. We identify host-derived peptides of 4-11 residues, varying in both charge and composition, as the substrates of PfCRT in vitro and in situ, and show that PfCRT does not mediate the non-specific transport of other metabolites and/or ions. We find that drug-resistance-conferring mutations reduce both the peptide transport capacity and substrate range of PfCRT, explaining the impaired fitness of drug-resistant parasites. Our results indicate that PfCRT transports peptides from the lumen of the parasite’s digestive vacuole to the cytosol, thereby providing a source of amino acids for parasite metabolism and preventing osmotic stress of this organelle. The resolution of PfCRT’s native substrates will aid the development of drugs that target PfCRT and/or restore the efficacy of existing antimalarials.

Date: 2020
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DOI: 10.1038/s41467-020-17781-6

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