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- The role of pfmdr1 in Plasmodium falciparum tolerance to artemether-lumefantrine in AfricaPublication . Sisowath, Christin; Ferreira, Pedro E.; Bustamante, Leyla Y.; Dahlstrom, Sabina; Martensson, Andreas; Bjorkman, Anders; Krishna, Sanjeev; Gil, José PedroObjective Artemether-lumefantrine (AL), presently the most favoured combination therapy against uncomplicated Plasmodium falciparum malaria in Africa, has recently shown to select for the pfmdr1 86N allele. The objective of this study was to search for the selection of other mutations potentially involved in artemether-lumefantrine tolerance and/or resistance, i.e. pfmdr1 gene amplification, pfmdr1 Y184F, S1034C, N1042D, D1246Y, pfcrt S163R and PfATP6 S769N. Methods The above mentioned SNPs were analysed by PCR-restriction fragment length polymorphism and pfmdr1 gene amplification by real-time PCR based protocols in parasites from 200 children treated with AL for uncomplicated P. falciparum malaria in Zanzibar. Results A statistically significant selection of pfmdr1 184F mostly in combination with 86N was seen in reinfections after treatment. No pfmdr1 gene amplification was found. Conclusion The results suggest that different pfmdr1 alleles are involved in the development of tolerance/resistance to lumefantrine.
- Plasmodium falciparum multidrug resistance protein 1 and artemisinin-based combination therapy in AfricaPublication . Dahlstrom, Sabina; Ferreira, Pedro; Veiga, Maria Isabel; Sedighi, Nazli; Wiklund, Lisa; Martensson, Andreas; Farnert, Anna; Sisowath, Christin; Osorio, Lyda; Darban, Hamid; Andersson, Bjoern; Kaneko, Akira; Conseil, Gwanaelle; Bjorkman, Anders; Gil, José PedroPlasmodium 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.