Plasmodium falciparumMultidrug Resistance Protein 1 and Artemisinin‐Based Combination Therapy in Africa

Abstract

Plasmodium falciparum response mechanisms to the major artemisinin-based combination therapies (ACTs) are largely unknown. Multidrug-resistance protein (MRP)-like adenosine triphosphate (ATP)-binding cassette transporters are known to be related to multidrug resistance in many organisms. Therefore, we hypothesized that sequence variation in pfmrp1 can contribute to decreased parasite sensitivity to ACT. Through sequencing of the pfmrp1 open reading frame for 103 geographically diverse P. falciparum infections, we identified 27 single-nucleotide polymorphisms (SNPs), of which 21 were nonsynonymous and 6 synonymous. Analyses of clinical efficacy trials with artesunate-amodiaquine and artemether-lumefantrine detected a specific selection of the globally prevalent I876V SNP in recurrent infections after artemether-lumefantrine treatment. Additional in silico studies suggested an influence of variation in amino acid 876 on the ATP hydrolysis cycle of pfMRP1 with potential impact on protein functionality. Our data suggest for the first time, to our knowledge, the involvement of pfMRP1 in P. falciparum in vivo response to ACT.

Whole-genome sequencing and microarray analysis of ex vivo Plasmodium vivax reveal selective pressure on putative drug resistance genes

“…In addition, knockouts of the gene in P. falciparum have rendered the parasites more sensitive to primaquine (40). It should be noted, however, that PfMRP1 has also been associated with artemisinin resistance in P. falciparum (53), and, therefore, PvMRP1 may be a general drug resistance protein. The data presented here coupled with data from P. falciparum suggest that pvmrp is a promising candidate for further evaluation.…”

The Management of Therapeutic Failure in a Falciparum Malaria Patient under Oral Arthemether-Lumefantrine Therapy

“…Bir çalışmada, Uganda'dan 5 hasta kanının da yer aldığı dünya genelinde falsiparum sıtmasının endemik olduğu Asya ve Afrika ülkelerinden 103 kan örneği toplanmış. Nested-PCR yöntemi ile pfMRP1'i kodlayan genin OPR (open reading frame) bölgesi sekanslanmış ve toplam 27 ayrı SNP (single nucleotid polymorphism) saptanmış olup özellikle I876V SNP'nin rekurrensten sorumlu olduğu hipotez edilmiştir (28). Bilinen en fazla direncin Asya kıtasında olmasıyla birlikte olgumuzun Uganda'dan import olmasından dolayı arthemether-lümefan-trin tedavi kombinasyonuna direnç durumu da düşünülmüştür ancak teknik aksaklıktan dolayı direnç analizi yapılamamıştır.…”

Optimization of a Ligase Detection Reaction-Fluorescent Microsphere Assay for Characterization of Resistance-Mediating Polymorphisms in African Samples of Plasmodium falciparum

“…We assessed sequences at 5 single nucleotide polymorphisms (SNPs) in pfmdr1 that are common in different parts of the world, a 5 amino acid haplotype in pfcrt that distinguishes chloroquine-sensitive and -resistant parasites with different geographic backgrounds, an SNP in pfmrp1 that is common in Africa and has been selected by prior treatment, 4 known SNPs in the antifolate target gene pfdhfr, and 5 known SNPs in the antifolate target gene pfdhps (7,14,15). Sequence determinations at all studied polymorphisms were unequivocal, generally with background readings for unidentified SNPs 5-to 10-fold lower than the readings for correct identifications (Fig.…”

“…For artemisinins, and for the ACT partner drugs mefloquine and lumefantrine, parasite drug sensitivity is mediated in part by polymorphisms in pfmdr1, but interestingly, polymorphisms that decrease sensitivity to aminoquinolines lead to increased sensitivity to these drugs (9,12,13). Polymorphisms in one additional putative drug transporter, pfmrp1, may play a role in mediating drug sensitivity; the pfmrp1 I876V polymorphism is prevalent in Africa, and the wild-type sequence was selected by prior treatment with artemether-lumefantrine (14). Resistance to SP is well characterized, with a series of mutations in the target enzymes dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) leading to stepwise acquisition of resistance (15).…”