Fusion of field studies and the laboratory solves a puzzle in antimalarial resistance

Sibley, Carol Hopkins; Lane, Kristin D.

doi:10.1073/pnas.1514403112

Cited by 2 publications

(1 citation statement)

References 23 publications

(17 reference statements)

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“…In this work, it was observed that Pfcrt -CVMNK were the favoured haplotypes. This can be attributed to compensatory mutation at C350R in a different study, which was shown to explain the seemingly discordant chloroquine response in Pfcrt -CVIET haplotype [ 45 ]. This may suggest the benefit of the two wild-type genes, Pfmdr1 -N 86 Y 184 and Pfcrt -CVMNK, was enhanced by the presence of artemisinin.…”

Section: Discussionmentioning

confidence: 99%

In vitro selection of Plasmodium falciparum Pfcrt and Pfmdr1 variants by artemisinin

Njokah

Kang’ethe

Kinyua

et al. 2016

Malar J

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BackgroundAnti-malarial drugs are the major focus in the prevention and treatment of malaria. Artemisinin-based combination therapy (ACT) is the WHO recommended first-line treatment for Plasmodium falciparum malaria across the endemic world. Also ACT is increasingly relied upon in treating Plasmodium vivax malaria where chloroquine is failing. The emergence of artemisinin drug-resistant parasites is a serious threat faced by global malaria control programmes. Therefore, the success of treatment and intervention strategies is highly pegged on understanding the genetic basis of resistance.MethodsHere, resistance in P. falciparum was generated in vitro for artemisinin to produce levels above clinically relevant concentrations in vivo, and the molecular haplotypes investigated. Genomic DNA was extracted using the QIAamp mini DNA kit. DNA sequences of Pfk13, Pfcrt and Pfmdr1 genes were amplified by PCR and the amplicons were successfully sequenced. Single nucleotide polymorphisms were traced by standard bidirectional sequencing and reading the transcripts against wild-type sequences in Codon code Aligner Version 5.1 and NCBI blast.ResultsExposure of parasite strains D6 and W2 to artemisinin resulted in a decrease in parasite susceptibility to artemisinin (W2 and D6) and lumefantrine (D6 only). The parasites exhibited elevated IC50s to multiple artemisinins, with >twofold resistance to artemisinin; however, the resistance index obtained with standard methods was noticeably less than expected for parasite lines recovered from 50 µg/ml 48 h drug pressure. The change in parasite susceptibility was associated with Pfmdr-185K mutation, a mutation never reported before. The Pfcrt-CVMNK genotype (Pfcrt codons 72–76) was retained and notably, the study did not detect any polymorphisms reported to reduce P. falciparum susceptibility in vivo in the coding sequences of the Pfk13 gene.DiscussionThis data demonstrate that P. falciparum has the capacity to develop resistance to artemisinin derivatives in vitro and that this phenotype is achieved by mutations in Pfmdr1, the genetic changes that are also underpinning lumefantrine resistance. This finding is of practical importance, because artemisinin drugs in Kenya are used in combination with lumefantrine for the treatment of malaria.ConclusionArtemisinin resistance phenotype as has been shown in this work, is a decrease in parasites susceptibility to artemisinin derivatives together with the parasite’s ability to recover from drug-induced dormancy after exposure to drug dosage above the in vivo clinical concentrations. The study surmises that Pfmdr1 may play a role in the anti-malarial activity of artemisinin.

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Section: Discussionmentioning

confidence: 99%

In vitro selection of Plasmodium falciparum Pfcrt and Pfmdr1 variants by artemisinin

Njokah

Kang’ethe

Kinyua

et al. 2016

Malar J

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The malaria parasite’s chloroquine resistance transporter: An exploration of its interactions with drugs and of its evolution as a drug transporter

Summers¹

2016

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Fusion of field studies and the laboratory solves a puzzle in antimalarial resistance

Cited by 2 publications

References 23 publications

In vitro selection of Plasmodium falciparum Pfcrt and Pfmdr1 variants by artemisinin

In vitro selection of Plasmodium falciparum Pfcrt and Pfmdr1 variants by artemisinin

The malaria parasite’s chloroquine resistance transporter: An exploration of its interactions with drugs and of its evolution as a drug transporter

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