Abstract
Antimalarial drug resistance hampers effective malaria treatment. Critical SNPs in a particular, putative amino acid transporter were recently linked to chloroquine (CQ) resistance in malaria parasites. Here, we show that this conserved protein (PF3D7_0629500 in Plasmodium falciparum; AAT1 in P. chabaudi) is a structural homologue of the yeast amino acid transporter Tat2p, which is known to mediate quinine uptake and toxicity. Heterologous expression of PF3D7_0629500 in yeast produced CQ hypersensitivity, coincident with increased CQ uptake. PF3D7_0629500-expressing cultures were also sensitized to related antimalarials; amodiaquine, mefloquine and particularly quinine. Drug sensitivity was reversed by introducing a SNP linked to CQ resistance in the parasite. Like Tat2p, PF3D7_0629500-dependent quinine hypersensitivity was suppressible with tryptophan, consistent with a common transport mechanism. A four-fold increase in quinine uptake by PF3D7_0629500 expressing cells was abolished by the resistance SNP. The parasite protein localised primarily to the yeast plasma membrane. Its expression varied between cells and this heterogeneity was used to show that high-expressing cell subpopulations were the most drug sensitive. The results reveal that the PF3D7_0629500 protein can determine the level of sensitivity to several major quinine-related antimalarials through an amino acid-inhibitable drug transport function. The potential clinical relevance is discussed.
Highlights
Associated with chloroquine resistance[11]
One problem with characterisation of drug transport and resistance mechanisms in malaria parasites is that not all of the relevant species are easy to cultivate in the laboratory or to manipulate genetically, improvements are being made including with P. falciparum[15,16]
The link between tryptophan and quinine action was successfully extended to malaria patients, where it was found that individuals with higher plasma tryptophan levels had a low incidence of adverse reactions to quinine[25]
Summary
Associated with chloroquine resistance[11]. Quinine resistance took over 200 years to emerge, but this is in striking contrast to other antimalarial drugs. Yeast genomic tools were used to reveal a novel mechanism of quinoline drug action, centred on cellular tryptophan (Trp) starvation. The earlier findings with yeast are exploited to test function of a Tat2p structural homologue that we identify in Plasmodium spp. It transpires that this homologue is a putative amino acid transporter in which SNPs were previously linked to chloroquine resistance in malaria parasites[27,28]. We successfully apply a yeast heterologous expression system to show that the parasite protein mediates uptake of quinoline drugs so altering the level of drug resistance. The evidence suggests a new quinoline-drug transport protein, which may help explain the protein’s association with drug resistance of the parasite
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