Heterologous Expression of a Novel Drug Transporter from the Malaria Parasite Alters Resistance to Quinoline Antimalarials

Sarah M. Tindall, Cindy Vallières, Dev H. Lakhani, Farida Hanim Islahudin, Kang Nee Ting, Simon V. Avery

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Article number2464
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - 1 Dec 2018

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Quinine
Antimalarials
Malaria
Chloroquine
Parasites
Single Nucleotide Polymorphism
Amino Acid Transport Systems
Pharmaceutical Preparations
Yeasts
Hypersensitivity
Amodiaquine
Mefloquine
Proteins
Plasmodium falciparum
Drug Resistance
Tryptophan
Cell Membrane
quinoline
Amino Acids

ASJC Scopus subject areas

  • General

Cite this

Heterologous Expression of a Novel Drug Transporter from the Malaria Parasite Alters Resistance to Quinoline Antimalarials. / Tindall, Sarah M.; Vallières, Cindy; Lakhani, Dev H.; Islahudin, Farida Hanim; Ting, Kang Nee; Avery, Simon V.

In: Scientific Reports, Vol. 8, No. 1, 2464, 01.12.2018.

Research output: Contribution to journalArticle

Tindall, Sarah M. ; Vallières, Cindy ; Lakhani, Dev H. ; Islahudin, Farida Hanim ; Ting, Kang Nee ; Avery, Simon V. / Heterologous Expression of a Novel Drug Transporter from the Malaria Parasite Alters Resistance to Quinoline Antimalarials. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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