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Science & Society | News | Globally prevalent mutations in Plasmodium falciparum modulate susceptibility to artemisinin-based combination therapies.

Globally prevalent mutations in Plasmodium falciparum modulate susceptibility to artemisinin-based combination therapies.

Main findings

Artemisinin-based combination therapies (ACTs) have been highly effective in recent years in treating Plasmodium falciparum infections and reducing the global burden of malaria.

The parasite transporter protein, P. falciparum multidrug resistance 1 protein (PfMDR1), has been long observed in molecular epidemiological studies to associate with altered parasite susceptibility to multiple ACT partner drugs. Leveraging recent advances in P. falciparum genome editing via the use of zinc-finger nucleases”, this study reports a definitive assessment of the PfMDR1 N-terminal mutations N86Y and Y184F, which are prevalent across malaria-endemic regions but which had previously not been amenable to transfection-based investigation.

Results show that the N86Y mutation contributes to resistance to some antimalarial drugs while sensitizing others.

This study also examined thousands of P. falciparum genomes to determine regional associations between PfMDR1 mutations, providing new insights into the ways in which drug pressures have shaped different parasite populations around the world.


Relevance/impact of this work for the society

The insights gained from these studies are both scientifically interesting in terms of the underlying mechanisms of resistance and drug action and of practical benefit in terms of optimizing treatments based on an understanding of clinical drug usage and haplotype distributions across endemic regions.


Future perspectives

These data, which resolve long-standing questions about the role of PfMDR1, provide a foundation for improved molecular surveillance of antimalarial drug resistance and help inform region-specific decisions on which ACTs to employ.

 Legend: Drug resistance threatens global efforts to reduce the malaria burden. Plasmodium falciparum susceptibility to artemisinin-based combination therapy partner drugs can be altered by a single amino acid change at position 86 from asparagine to tyrosine (shown in red) in the parasite transporter PfMDR1.

 

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Researcher contact

Maria Isabel Veiga

Email: mariaveiga@ecsaude.uminho.pt 

Phone: 253604883

 

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