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MRP1 mediates folate transport and antifolate sensitivity in Plasmodium falciparum

Sanna R Rijpma1, Maarten van der Velden1, Albert Bilos1

  • 1Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.

FEBS Letters
|February 23, 2016
PubMed

Insights

Multidrug resistance-associated proteins (MRP) in Plasmodium falciparum export folate, impacting drug sensitivity. Lack of MRP1 reduces folate levels and sensitivity to antifolates like methotrexate, crucial for malaria treatment.

Area of Science:

  • Parasitology
  • Molecular Biology
  • Drug Resistance

Background:

  • Multidrug resistance-associated proteins (MRP) in Plasmodium falciparum are linked to altered drug sensitivity.
  • Understanding MRP substrate specificity is key to characterizing resistance mechanisms and parasite physiology.

Purpose of the Study:

  • To investigate the role of Plasmodium falciparum MRP1 in folate transport and its impact on drug sensitivity.
  • To elucidate the physiological functions of MRPs in malaria parasites.

Main Methods:

  • Untargeted metabolomics approach.
  • Analysis of red blood cells infected with schizont stage parasites lacking MRP1 expression.
  • Drug sensitivity testing using the folate analog methotrexate.

Main Results:

  • Decreased folate concentrations were detected in red blood cells infected with parasites lacking MRP1.
  • Parasites lacking MRP1 exhibited a tenfold decrease in sensitivity to methotrexate.
  • PfMRP1 facilitates the export of folate from parasites into red blood cells.

Conclusions:

  • PfMRP1 plays a significant role in folate homeostasis within malaria parasites.
  • PfMRP1 is a critical factor for parasite sensitivity to antifolate drugs.
  • Targeting PfMRP1 or the folate pathway could be a viable strategy for malaria treatment.
Keywords:
ABC transporterPlasmodium falciparumfolatemultidrug resistance proteinmultidrug resistance-associated proteins

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