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Heterologous expression of a novel drug transporter from the malaria parasite alters resistance to quinoline antimalarials

Tindall, Sarah M.; Valli�res, Cindy; Lakhani, Dev H.; Islahudin, Farida; Ting, Kang-Nee; Avery, Simon V.

Authors

Sarah M. Tindall

Cindy Valli�res

Dev H. Lakhani

Farida Islahudin

Kang-Nee Ting

SIMON AVERY SIMON.AVERY@NOTTINGHAM.AC.UK
Professor of Eukaryotic Microbiology



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.

Citation

Tindall, S. M., Vallières, C., Lakhani, D. H., Islahudin, F., Ting, K., & Avery, S. V. (in press). Heterologous expression of a novel drug transporter from the malaria parasite alters resistance to quinoline antimalarials. Scientific Reports, 8(1), https://doi.org/10.1038/s41598-018-20816-0

Journal Article Type Article
Acceptance Date Jan 22, 2018
Online Publication Date Feb 6, 2018
Deposit Date Feb 7, 2018
Publicly Available Date Mar 28, 2024
Journal Scientific Reports
Electronic ISSN 2045-2322
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 8
Issue 1
DOI https://doi.org/10.1038/s41598-018-20816-0
Public URL https://nottingham-repository.worktribe.com/output/909854
Publisher URL https://www.nature.com/articles/s41598-018-20816-0

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