Plasmodium falciparum Multidrug Resistance Proteins (pf MRPs)

Abstract

The capacity of the lethal Plasmodium falciparum parasite to develop resistance against anti-malarial drugs represents a central challenge in the global control and elimination of malaria. Historically, the action of drug transporters is known to play a pivotal role in the capacity of the parasite to evade drug action. MRPs (Multidrug Resistance Protein) are known in many phylogenetically diverse groups to be related to drug resistance by being able to handle a large range of substrates, including important endogenous substances as glutathione and its conjugates. P. falciparum MRPs are associated with in vivo and in vitro altered drug response, and might be important factors for the development of multi-drug resistance phenotypes, a latent possibility in the present, and future, combination therapy environment. Information on P. falciparum MRPs is scattered in the literature, with no specialized review available. We herein address this issue by reviewing the present state of knowledge.

Keywords: ABC protein; MRP; Plasmodium falciparum; malaria; multidrug resistance.

FIGURE 1

Compilation of non-synonymous SNPs in pfMRP1 (A) and pfMRP2 (B). This was based on MalariaGen and the article list of bibliographic references. SNPs in bold correspond to alleles with frequencies above 1%, according to the MalariaGen Community Project. In bold red, SNPs that have been reported as associated with parasite drug response (see main text and Table 1). Boxes in orange denote transmembrane domains (Dahlstrom et al., 2009; Veiga et al., 2014). Blue boxes in the pfMRP2 figure correspond to micro-indel (MI) regions comprising variable tandem repeat regions (Veiga et al., 2014). MI-III has been observed to be associated with lumefantrine response (Okombo et al., 2013), being as such also marked in bold red. To note the trend for SNP hotspots in pfMRP2.

FIGURE 2

Possible contributions of pfMRP1 to drug resistance. pfMRP1 is essentially located in the parasite plasma membrane, putatively transporting antimalarial drugs. This action can be particularly important (and sufficient) concerning resistance to antimalarials which targets reside mainly in the cytosol or in the plasma membrane (e.g. mefloquine, that has been proposed to affect the phagocytosis of hemoglobin). Here, it might work in conjugation with Pgh, located in the food vacuole. For the more food vacuole centric antimalarials, namely 4-aminoquinolines (CQ, DEAQ), pfMRP1 might act as a second step in a two phase system of efflux. Also, resilience against antimalarials might include the role of pfMRP1 in the protective functions of the glutathione metabolism, through the efflux of its oxidized form (GSSG). This is expected to be important, as many antimalarials exert oxidative stress in the parasite, namely through increased levels of free heme. Finally, the pfMRP1 capacity of transporting folate is suggested to drive the involvement of this protein in antifolate resistance, by participating in the import of folate, which will directly compete with antifolate drugs for their target. Increases in intracellular pool will lead to less drug action. (LUM, lumefantrine; MQ, mefloquine; CQ, chloroquine; Pyr, pyrimethamine; AAQ, aminoalcohol quinolone; 4-AQN, 4-aminoquinoline; QN, quinine; MTX, methotrexate; Pgh, P-glycoprotein homologue; CRT, chlroquine resistance transporter).