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Novel polymorphisms in Plasmodium falciparum ABC transporter genes are associated with major ACT antimalarial drug resistance.

Veiga MI, Ferreira PE, Jörnhagen L, Malmberg M, Kone A, Schmidt BA, Petzold M, Björkman A, Nosten F, Gil JP - PLoS ONE (2011)

Bottom Line: The previously unstudied pfmdr1 F1226Y and pfmrp1 F1390I SNPs were associated significantly with artemisinin, mefloquine and lumefantrine in vitro susceptibility.A variation in pfmdr1 gene copy number was also associated with parasite drug susceptibility of artemisinin, mefloquine and lumefantrine.Our work unveils new candidate markers of P. falciparum multidrug resistance in vitro, while contributing to the understanding of subjacent genetic complexity, essential for future evidence-based drug policy decisions.

View Article: PubMed Central - PubMed

Affiliation: Malaria Research Lab, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. Isabel.veiga@ki.se

ABSTRACT
Chemotherapy is a critical component of malaria control. However, the most deadly malaria pathogen, Plasmodium falciparum, has repeatedly mounted resistance against a series of antimalarial drugs used in the last decades. Southeast Asia is an epicenter of emerging antimalarial drug resistance, including recent resistance to the artemisinins, the core component of all recommended antimalarial combination therapies. Alterations in the parasitic membrane proteins Pgh-1, PfCRT and PfMRP1 are believed to be major contributors to resistance through decreasing intracellular drug accumulation. The pfcrt, pfmdr1 and pfmrp1 genes were sequenced from a set of P.falciparum field isolates from the Thai-Myanmar border. In vitro drug susceptibility to artemisinin, dihydroartemisinin, mefloquine and lumefantrine were assessed. Positive correlations were seen between the in vitro susceptibility responses to artemisinin and dihydroartemisinin and the responses to the arylamino-alcohol quinolines lumefantrine and mefloquine. The previously unstudied pfmdr1 F1226Y and pfmrp1 F1390I SNPs were associated significantly with artemisinin, mefloquine and lumefantrine in vitro susceptibility. A variation in pfmdr1 gene copy number was also associated with parasite drug susceptibility of artemisinin, mefloquine and lumefantrine. Our work unveils new candidate markers of P. falciparum multidrug resistance in vitro, while contributing to the understanding of subjacent genetic complexity, essential for future evidence-based drug policy decisions.

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Related in: MedlinePlus

Proposed model for mode of action of the polymorphisms found.The central assumption is that ART, LUM and MQ drugs have their main pharmacological targets located in the cytoplasmic compartment while PfMRP1, operates by reducing the intra-cytoplasmatic concentrations by effluxing them out of the cell. Pgh-1, on its turn will contribute to further drug expulsion from the cytoplasm by transporting these drugs towards the lumen of the food vacuole.
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pone-0020212-g007: Proposed model for mode of action of the polymorphisms found.The central assumption is that ART, LUM and MQ drugs have their main pharmacological targets located in the cytoplasmic compartment while PfMRP1, operates by reducing the intra-cytoplasmatic concentrations by effluxing them out of the cell. Pgh-1, on its turn will contribute to further drug expulsion from the cytoplasm by transporting these drugs towards the lumen of the food vacuole.

Mentions: The precise mechanistic contribution of each one of these mutations remains an open question. From our results and others, a simple model compiling the available data can be proposed (figure 7), partly extending from previous suggestions [17], [22], [29]. The central assumption is that ART, LUM and MQ drugs have their main pharmacological targets located in the cytoplasmic compartment [29] while PfMRP1, located in the plasma membrane, pumps them out of the cell, thereby reducing the intra-cytoplasmatic concentrations of the drugs. Pgh-1, inserted in the food vacuole membrane, would contribute to further drug expulsion from the cytoplasm by transporting these drugs towards the lumen of this organelle.


Novel polymorphisms in Plasmodium falciparum ABC transporter genes are associated with major ACT antimalarial drug resistance.

Veiga MI, Ferreira PE, Jörnhagen L, Malmberg M, Kone A, Schmidt BA, Petzold M, Björkman A, Nosten F, Gil JP - PLoS ONE (2011)

Proposed model for mode of action of the polymorphisms found.The central assumption is that ART, LUM and MQ drugs have their main pharmacological targets located in the cytoplasmic compartment while PfMRP1, operates by reducing the intra-cytoplasmatic concentrations by effluxing them out of the cell. Pgh-1, on its turn will contribute to further drug expulsion from the cytoplasm by transporting these drugs towards the lumen of the food vacuole.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3102103&req=5

pone-0020212-g007: Proposed model for mode of action of the polymorphisms found.The central assumption is that ART, LUM and MQ drugs have their main pharmacological targets located in the cytoplasmic compartment while PfMRP1, operates by reducing the intra-cytoplasmatic concentrations by effluxing them out of the cell. Pgh-1, on its turn will contribute to further drug expulsion from the cytoplasm by transporting these drugs towards the lumen of the food vacuole.
Mentions: The precise mechanistic contribution of each one of these mutations remains an open question. From our results and others, a simple model compiling the available data can be proposed (figure 7), partly extending from previous suggestions [17], [22], [29]. The central assumption is that ART, LUM and MQ drugs have their main pharmacological targets located in the cytoplasmic compartment [29] while PfMRP1, located in the plasma membrane, pumps them out of the cell, thereby reducing the intra-cytoplasmatic concentrations of the drugs. Pgh-1, inserted in the food vacuole membrane, would contribute to further drug expulsion from the cytoplasm by transporting these drugs towards the lumen of this organelle.

Bottom Line: The previously unstudied pfmdr1 F1226Y and pfmrp1 F1390I SNPs were associated significantly with artemisinin, mefloquine and lumefantrine in vitro susceptibility.A variation in pfmdr1 gene copy number was also associated with parasite drug susceptibility of artemisinin, mefloquine and lumefantrine.Our work unveils new candidate markers of P. falciparum multidrug resistance in vitro, while contributing to the understanding of subjacent genetic complexity, essential for future evidence-based drug policy decisions.

View Article: PubMed Central - PubMed

Affiliation: Malaria Research Lab, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. Isabel.veiga@ki.se

ABSTRACT
Chemotherapy is a critical component of malaria control. However, the most deadly malaria pathogen, Plasmodium falciparum, has repeatedly mounted resistance against a series of antimalarial drugs used in the last decades. Southeast Asia is an epicenter of emerging antimalarial drug resistance, including recent resistance to the artemisinins, the core component of all recommended antimalarial combination therapies. Alterations in the parasitic membrane proteins Pgh-1, PfCRT and PfMRP1 are believed to be major contributors to resistance through decreasing intracellular drug accumulation. The pfcrt, pfmdr1 and pfmrp1 genes were sequenced from a set of P.falciparum field isolates from the Thai-Myanmar border. In vitro drug susceptibility to artemisinin, dihydroartemisinin, mefloquine and lumefantrine were assessed. Positive correlations were seen between the in vitro susceptibility responses to artemisinin and dihydroartemisinin and the responses to the arylamino-alcohol quinolines lumefantrine and mefloquine. The previously unstudied pfmdr1 F1226Y and pfmrp1 F1390I SNPs were associated significantly with artemisinin, mefloquine and lumefantrine in vitro susceptibility. A variation in pfmdr1 gene copy number was also associated with parasite drug susceptibility of artemisinin, mefloquine and lumefantrine. Our work unveils new candidate markers of P. falciparum multidrug resistance in vitro, while contributing to the understanding of subjacent genetic complexity, essential for future evidence-based drug policy decisions.

Show MeSH
Related in: MedlinePlus