Decreasingpfmdr1Copy Number inPlasmodium falciparumMalaria Heightens Susceptibility to Mefloquine, Lumefantrine, Halofantrine, Quinine, and Artemisinin

Abstract

The global dissemination of drug-resistant Plasmodium falciparum is spurring intense efforts to implement artemisinin (ART)-based combination therapies for malaria, including mefloquine (MFQ)-artesunate and lumefantrine (LUM)-artemether. Clinical studies have identified an association between an increased risk of MFQ, MFQ-artesunate, and LUM-artemether treatment failures and pfmdr1 gene amplification. To directly address the contribution that pfmdr1 copy number makes to drug resistance, we genetically disrupted 1 of the 2 pfmdr1 copies in the drug-resistant FCB line, which resulted in reduced pfmdr1 mRNA and protein expression. These knockdown clones manifested a 3-fold decrease in MFQ IC(50) values, compared with that for the FCB line, verifying the role played by pfmdr1 expression levels in mediating resistance to MFQ. These clones also showed increased susceptibility to LUM, halofantrine, quinine, and ART. No change was observed for chloroquine. These results highlight the importance of pfmdr1 copy number in determining P. falciparum susceptibility to multiple agents currently being used to combat malaria caused by multidrug-resistant parasites.

Distribution of Drug Resistance Genotypes in Plasmodium falciparum in an Area of Limited Parasite Diversity in Saudi Arabia

“…35,47 Mutations at codon 86 have been associated with CQR, 35,47 whereas mutations at codons 184, 1034, 1042, and 1246 have been implicated to varying degrees in resistance to mefloquine and artesunate. 35,[47][48][49][50] An increased association between artesunate-mefloquine failure and a mutation at codon 184 has been seen in P. falciparum parasites in Cambodia. 51 However, it is unlikely that the high frequency of mutations at codon 184 in the Jazan area is linked to mefloquine resistance, because this drug has not been in common use.…”

Declining Artesunate-Mefloquine Efficacy against Falciparum Malaria on the Cambodia–Thailand Border

“…When artesunate was fi rst introduced in the early 1990s, failure to clear parasites by 48 hours was rare among patients with uncomplicated falciparum malaria in southeastern Thailand. Additionally, increased copy numbers of pfmdr1 gene have recently been shown to be associated with in vitro resistance to artemisinin (and to lumefantrine and quinine) (13).…”

Polimorfismos del gen pfmdr1 en muestras clínicas de Plasmodium falciparum y su relación con la respuesta terapéutica a antipalúdicos y paludismo grave en Colombia

“…Algunos autores han reportado aumento en el número de copias del gen pfmdr1 como factor determinante crucial de la resistencia in vitro y de la falla al tratamiento a mefloquina (15,43,44) y su disminución, como determinante en el aumento de la sensibilidad de P. falciparum a múltiples antipalúdicos (45). El estudio de este fenómeno no era el objeto de este estudio, pero, a la luz de nuestros resultados y los de otros autores (46), parece lógico explorar tanto el número de copias como los niveles de expresión del gen en algunas de las muestras.…”