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

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.

Genetic and chemical validation of Plasmodium falciparum aminopeptidase PfA-M17 as a drug target in the hemoglobin digestion pathway

“…PfA-M17 is a 68 kDa cytoplasmic enzyme that forms a homo-hexamer in its active form, with optimal function at neutral pH, similar to the pH of the parasite cytoplasm (20)(21)(22). Mathew et al (2021) recently confirmed the cytoplasmic localization of PfA-M17, which supports the proposition that hemoglobin-derived peptides are exported from the DV into the parasite cytoplasm, either through the chloroquine-resistance transporter or by other unidentified mechanisms (23). Once in the cytoplasm, it is believed that hemoglobin-derived peptides are digested by PfA-M17, however, it is also possible that PfA-M17 plays an additional role in the catabolic turnover of peptides from other origins.…”

Chloroquine and Sulfadoxine–Pyrimethamine Resistance in Sub-Saharan Africa—A Review

“…CQ is able to move through biological membranes and accumulate in the acidic digestive vacuole (Ehlgen et al, 2012). This digestive vacuole functions to conduct Polymorphism at position 76 (K76T) in the first transmembrane domain (Pulcini et al, 2015) Digestive vacuole (Shafik et al, 2020) Mutant Pfcrt-mediated CQ efflux lessens access of CQ to its heme target (Ecker et al, 2012) pfmdr-1 [located on chromosome 5 (Ikegbunam et al, 2019)]…”

A Virulence Associated Siderophore Importer Reduces Antimicrobial Susceptibility of Klebsiella pneumoniae

“…Broad-specificity multidrug efflux pumps are an apparent exception, and these have binding cavities with multiple sites that can interact with diverse antimicrobials ( Du et al, 2018 ). Other rare examples of bispecific or multispecific unidirectional transport have been reported in bacteria and eukaryotes, such as siderophore export by multidrug efflux pumps, antibiotic entry through an asparagine importer, and chloroquine transport by a plasmodium peptide transporter ( Hannauer et al, 2012 ; Smith et al, 2019 ; Shafik et al, 2020 ). By contrast, bidirectional ABC transporters that import one substrate and export another, are compatible with the mechanistic models but are unknown.…”