Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number

Abstract

Multidrug resistant P falciparum malaria is common in southeast Asia, but difficult to identify and treat. Genes that encode parasite transport proteins maybe involved in export of drugs and so cause resistance. In this study we show that increase in copy number of pfmdr1, a gene encoding a parasite transport protein, is the best overall predictor of treatment failure with mefloquine. Increase in pfmdr1 copy number predicts failure even after chemotherapy with the highly effective combination of mefloquine and 3 days' artesunate. Monitoring of pfmdr1 copy number will be useful in epidemiological surveys of drug resistance in P falciparum, and potentially for predicting treatment failure in individual patients.

Amodiaquine resistance in Plasmodium berghei is associated with PbCRT His95Pro mutation, loss of chloroquine, artemisinin and primaquine sensitivity, and high transcript levels of key transporters

“…Mutation at positions 86, 184, 1034, 1042, and 1246 in Pfmdr1 mediate and/or modulate CQ, LM and mefloquine resistance ( Ecker et al , 2012; Price et al , 1999; Price et al , 2004; Sisowath et al , 2005). Studies in the rodent malaria Plasmodium chabaudi found no association between crt and CQ resistance ( Afonso et al , 2006; Hunt et al , 2004).…”

Lack of multiple copies of pfmdr1 gene in Papua New Guinea

“…The pfmdr1 gene copy number was assessed as described previously (Price et al, 2004). The assays were run in triplicate on an Applied Biosystems 7500 real-time PCR system (Applied Biosystems, Rotkreuz, Switzerland) and every run contained two calibrator DNA samples from clones 3D7 and W2-mef, having pfmdr1 copy numbers of 1 and 3, respectively.…”

“…The Ct threshold was set manually at 0.05 for pfmdr1 and at 0.03 for ␤-tubulin, respectively, and the baseline was calculated automatically. Results were analysed by the comparative Ct method described previously (Price et al, 2004). Assays were repeated if one of the following results was obtained: no Ct value for more than one sample in the triplicate; calibrator copy number / = 3; Ct spread >1.5; Ct values >35.…”

“…Recent in vitro and in vivo studies showed an association between artesunate-mefloquine therapy failure and genetic changes in Plasmodium falciparum multidrug resistance protein 1 (pfmdr1) gene (Price et al, 2004;Sidhu et al, 2006). These findings underline the contribution of pfmdr1 copy number to the susceptibility of P. falciparum to antimalarial drugs.…”

Étude de la résistance dePlasmodium falciparumaux antipaludiques au sein du réseau international des Instituts Pasteur (RIIP-Palu)

“…La protéine PfMDR-1 est impliquée dans la modulation de la sensibilité à de multiples antipaludiques et, plus particulièrement, dans l'efflux des antipaludiques hydrophobes [45]. Les mécanismes de résistance sont liés : (1) soit à des phénomènes de duplication, entraînant une augmentation de l'expression de la protéine [46] et la résistance aux aryl-amino-alcool (comme la méflo-quine ou la luméfantrine) et une baisse de sensibilité aux dérivés de l'artémisinine (mais sans lien statistiquement établi avec l'efficacité clinique des ACT [47][48][49]) ; (2) soit à l'apparition de mutations au niveau des codons 86 (NY), 184 (YF), 1034 (SC), 1042 (ND) et 1246 (DY), entraînant une altération de sensibilité des parasites à certains antipaludiques comme les amino-4-quinoléines [45]. Il existe un effet antagoniste entre la sensibilité à la chloroquine et à la méfloquine : la mutation 86Y diminue la sensibilité des parasites à la chloroquine, mais augmente celle de la méfloquine.…”