scholarly journals Expansion of a Specific Plasmodium falciparum PfMDR1 Haplotype in Southeast Asia with Increased Substrate Transport

mBio ◽  
2020 ◽  
Vol 11 (6) ◽  
Author(s):  
Carla Calçada ◽  
Miguel Silva ◽  
Vitória Baptista ◽  
Vandana Thathy ◽  
Rita Silva-Pedrosa ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Southeast Asia ◽  
Gene Copy ◽  
Multidrug Resistance Protein ◽  
Combination Therapies ◽  
Transport Capacity ◽  
Multidrug Resistance Protein 1 ◽  
Content Type ◽  
Resistance Protein

ABSTRACT Artemisinin-based combination therapies (ACTs) have been vital in reducing malaria mortality rates since the 2000s. Their efficacy, however, is threatened by the emergence and spread of artemisinin resistance in Southeast Asia. The Plasmodium falciparum multidrug resistance protein 1 (PfMDR1) transporter plays a central role in parasite resistance to ACT partner drugs through gene copy number variations (CNV) and/or single nucleotide polymorphisms (SNPs). Using genomic epidemiology, we show that multiple pfmdr1 copies encoding the N86 and 184F haplotype are prevalent across Southeast Asia. Applying genome editing tools on the Southeast Asian Dd2 strain and using a surrogate assay to measure transporter activity in infected red blood cells, we demonstrate that parasites harboring multicopy N86/184F PfMDR1 have a higher Fluo-4 transport capacity compared with those expressing the wild-type N86/Y184 haplotype. Multicopy N86/184F PfMDR1 is also associated with decreased parasite susceptibility to lumefantrine. These findings provide evidence of the geographic selection and expansion of specific multicopy PfMDR1 haplotypes associated with multidrug resistance in Southeast Asia. IMPORTANCE Global efforts to eliminate malaria depend on the continued success of artemisinin-based combination therapies (ACTs) that target Plasmodium asexual blood-stage parasites. Resistance to ACTs, however, has emerged, creating the need to define the underlying mechanisms. Mutations in the P. falciparum multidrug resistance protein 1 (PfMDR1) transporter constitute an important determinant of resistance. Applying gene editing tools combined with an analysis of a public database containing thousands of parasite genomes, we show geographic selection and expansion of a pfmdr1 gene amplification encoding the N86/184F haplotype in Southeast Asia. Parasites expressing this PfMDR1 variant possess a higher transport capacity that modulates their responses to antimalarials. These data could help tailor and optimize antimalarial drug usage in different regions where malaria is endemic by taking into account the regional prevalence of pfmdr1 polymorphisms.

scholarly journals A Computational Approach towards the Understanding of Plasmodium falciparum Multidrug Resistance Protein 1

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Saumya K. Patel ◽  
Linz-Buoy George ◽  
Sivakumar Prasanth Kumar ◽  
Hyacinth N. Highland ◽  
Yogesh T. Jasrai ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Resistance Mechanism ◽  
Structural Motif ◽  
Multidrug Resistance Protein ◽  
Mutant Type ◽  
Multidrug Resistance Protein 1 ◽  
Antimalarial Resistance ◽  
Resistant Strains ◽  
Resistance Protein

The emergence of drug resistance in Plasmodium falciparum tremendously affected the chemotherapy worldwide while the intense distribution of chloroquine-resistant strains in most of the endemic areas added more complications in the treatment of malaria. The situation has even worsened by the lack of molecular mechanism to understand the resistance conferred by Plasmodia species. Recent studies have suggested the association of antimalarial resistance with P. falciparum multidrug resistance protein 1 (PfMDR1), an ATP-binding cassette (ABC) transporter and a homologue of human P-glycoprotein 1 (P-gp1). The present study deals about the development of PfMDR1 computational model and the model of substrate transport across PfMDR1 with insights derived from conformations relative to inward- and outward-facing topologies that switch on/off the transportation system. Comparison of ATP docked positions and its structural motif binding properties were found to be similar among other ATPases, and thereby contributes to NBD domains dimerization, a unique structural agreement noticed in Mus musculus Pgp and Escherichia coli MDR transporter homolog (MsbA). The interaction of leading antimalarials and phytochemicals within the active pocket of both wild-type and mutant-type PfMDR1 demonstrated the mode of binding and provided insights of less binding affinity thereby contributing to parasite’s resistance mechanism.

scholarly journals Complex Polymorphisms in the Plasmodium falciparum Multidrug Resistance Protein 2 Gene and Its Contribution to Antimalarial Response

2014 ◽  
Vol 58 (12) ◽  
pp. 7390-7397 ◽  
Author(s):  
Maria Isabel Veiga ◽  
Nuno S. Osório ◽  
Pedro Eduardo Ferreira ◽  
Oscar Franzén ◽  
Sabina Dahlstrom ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Abc Transporter ◽  
Parasite Clearance ◽  
Antimalarial Drugs ◽  
Multidrug Resistance Protein ◽  
Content Type ◽  
Resistance Protein

ABSTRACTPlasmodium falciparumhas the capacity to escape the actions of essentially all antimalarial drugs. ATP-binding cassette (ABC) transporter proteins are known to cause multidrug resistance in a large range of organisms, including theApicomplexaparasites.P. falciparumgenome analysis has revealed two genes coding for the multidrug resistance protein (MRP) type of ABC transporters:Pfmrp1, previously associated with decreased parasite drug susceptibility, and the poorly studiedPfmrp2. The role ofPfmrp2polymorphisms in modulating sensitivity to antimalarial drugs has not been established. We herein report a comprehensive account of thePfmrp2genetic variability in 46 isolates from Thailand. A notably high frequency of 2.8 single nucleotide polymorphisms (SNPs)/kb was identified for this gene, including some novel SNPs. Additionally, we found thatPfmrp2harbors a significant number of microindels, some previously not reported. We also investigated the potential association of the identifiedPfmrp2polymorphisms with alteredin vitrosusceptibility to several antimalarials used in artemisinin-based combination therapy and with parasite clearance time. Association analysis suggestedPfmrp2polymorphisms modulate the parasite'sin vitroresponse to quinoline antimalarials, including chloroquine, piperaquine, and mefloquine, and association within vivoparasite clearance. In conclusion, our study reveals that thePfmrp2gene is the most diverse ABC transporter known inP. falciparumwith a potential role in antimalarial drug resistance.

scholarly journals Multidrug resistance protein 1 regulates lipid asymmetry in erythrocyte membranes

2000 ◽  
Vol 350 (2) ◽  
pp. 531-535 ◽  
Author(s):  
David W. C. DEKKERS ◽  
Paul COMFURIUS ◽  
Rein G. J. VAN GOOL ◽  
Edouard M. BEVERS ◽  
Robert F. A. ZWAAL
Keyword(s):  
Multidrug Resistance ◽  
Erythrocyte Membrane ◽  
Erythrocyte Membranes ◽  
Multidrug Resistance Protein ◽  
Multidrug Resistance Protein 1 ◽  
Lipid Asymmetry ◽  
Appreciable Change ◽  
Outer Leaflet ◽  
Resistance Protein ◽  
Phospholipid Distribution

The role of multidrug resistance protein 1 (MRP1) in the maintenance of transbilayer lipid asymmetry in the erythrocyte membrane was investigated. The transbilayer distribution of endogenous phospholipids and [(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]hexanoyl (NBD)-labelled lipid analogues was compared in the absence and the presence of inhibitors of MRP1. At equilibrium the transbilayer distribution of the NBD analogues (in the absence of MRP1 inhibitors) was very similar to that of the endogenous lipids. Inhibition of MRP1 by verapamil or indomethacin resulted in a shift in the amount of probe that was internalized: approx. 50% of NBD-labelled phosphatidylcholine (PtdCho) and 9% of NBD-sphingomyelin (NBD-Spm) were no longer extractable by BSA in cells treated with inhibitor, in comparison with 25% and 3% for control cells respectively. To verify whether inhibition of MRP1 also affected the distribution of the endogenous phospholipids, phospholipase A2 and sphingomyelinase were used to assess the amount of each of the various lipid classes present in the membrane outer leaflet. No shift in phospholipid distribution was observed after 5h of incubation with verapamil or indomethacin. However, after 48h of incubation with these inhibitors, significantly smaller amounts of PtdCho and Spm were present in the outer membrane leaflet. No appreciable change was observed in the distribution of phosphatidylethanolamine or phosphatidylserine. Decreased hydrolysis of PtdCho and Spm was not due to endovesicle formation, as revealed by electron microscopy. This is the first report to show that MRP1 has a role in the maintenance of the outwards orientation of endogenous choline-containing phospholipids in the erythrocyte membrane.

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