Tolerance of Plasmodium falciparum mefloquine-resistant clinical isolates to mefloquine-piperaquine with implications for triple artemisinin-based combination therapies

Camille Roesch, Anna Cosson, Melissa Mairet Khedim, Nimol Khim, Nimol Kloeung, Sopheakvatey Ke, Sreynet Srun, Rotha Eam, Chanra Khean, Chanvong Kul, Lucie Adoux, Jean Popovici, Rithea Leang, Pascal Ringwald, Frédéric Ariey, Romain Coppée and Benoit Witkowski ()
Additional contact information
Camille Roesch: Pasteur Institute of Cambodia, Malaria Unit
Anna Cosson: Université de Rouen Normandie, Laboratoire de Parasitologie-Mycologie, UR ESCAPE
Melissa Mairet Khedim: Pasteur Institute of Cambodia, Malaria Unit
Nimol Khim: Pasteur Institute of Cambodia, Malaria Unit
Nimol Kloeung: Pasteur Institute of Cambodia, Malaria Unit
Sopheakvatey Ke: Pasteur Institute of Cambodia, Malaria Unit
Sreynet Srun: Pasteur Institute of Cambodia, Malaria Unit
Rotha Eam: Pasteur Institute of Cambodia, Malaria Unit
Chanra Khean: Pasteur Institute of Cambodia, Malaria Unit
Chanvong Kul: Pasteur Institute of Cambodia, Malaria Unit
Lucie Adoux: Institut Cochin, GENOM’IC, Université Paris Cité, CNRS, INSERM
Jean Popovici: Pasteur Institute of Cambodia, Malaria Unit
Rithea Leang: Ministry of Health, National Center for Parasitology, Entomology, and Malaria Control
Pascal Ringwald: WHO, Mekong Malaria Elimination Programme
Frédéric Ariey: Université Paris Cité, INSERM U1344, MERIT IRD
Romain Coppée: Université de Rouen Normandie, Laboratoire de Parasitologie-Mycologie, UR ESCAPE
Benoit Witkowski: Pasteur Institute of Cambodia, Malaria Unit

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract Triple artemisinin-based combination therapies (TACTs) have been proposed to delay the emergence of multidrug-resistant Plasmodium falciparum by combining two partner drugs with an artemisinin derivative. Among these, mefloquine–piperaquine (MQ–PPQ) is a leading candidate, based on the assumption that simultaneous resistance to both partner drugs would be difficult to develop. Here, we assess the efficacy and resistance potential of MQ–PPQ using Cambodian clinical isolates with distinct resistance profiles. We find that MQ resistance confers significant cross-tolerance to the MQ–PPQ combination, whereas PPQ-resistant and -sensitive strains remain susceptible. Under repeated MQ–PPQ pressure for four months, parasites rapidly acquire MQ–PPQ tolerance, driven by pfmdr1 amplification. Mechanistic investigations reveal that MQ inhibits PPQ accumulation in a dose-dependent manner, providing a functional explanation for the compromised efficacy of the combination. These findings demonstrate that MQ resistance alone can undermine MQ–PPQ TACT efficacy, calling into question the strategic rationale of this combination and underscoring the need for alternative regimens with a lower risk of resistance selection.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-65629-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65629-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-65629-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().