{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:47:35Z","timestamp":1787003255460,"version":"build-2736575974"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100004417","name":"Global Fund to Fight AIDS, Tuberculosis and Malaria","doi-asserted-by":"publisher","award":["RAI3E"],"award-info":[{"award-number":["RAI3E"]}],"id":[{"id":"10.13039\/100004417","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Triple artemisinin-based combination therapies (TACTs) have been proposed to delay the emergence of multidrug-resistant\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    by combining two partner drugs with an artemisinin derivative. Among these, mefloquine\u2013piperaquine (MQ\u2013PPQ) 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\u2013PPQ using Cambodian clinical isolates with distinct resistance profiles. We find that MQ resistance confers significant cross-tolerance to the MQ\u2013PPQ combination, whereas PPQ-resistant and -sensitive strains remain susceptible. Under repeated MQ\u2013PPQ pressure for four months, parasites rapidly acquire MQ\u2013PPQ tolerance, driven by\n                    <jats:italic>pfmdr1<\/jats:italic>\n                    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\u2013PPQ 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.\n                  <\/jats:p>","DOI":"10.1038\/s41467-025-65629-8","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T13:55:07Z","timestamp":1764251707000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Tolerance of Plasmodium falciparum mefloquine-resistant clinical isolates to mefloquine-piperaquine with implications for triple artemisinin-based combination therapies"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5119-0655","authenticated-orcid":false,"given":"Camille","family":"Roesch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Cosson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Mairet Khedim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nimol","family":"Khim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nimol","family":"Kloeung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sopheakvatey","family":"Ke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sreynet","family":"Srun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rotha","family":"Eam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanra","family":"Khean","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanvong","family":"Kul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Adoux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3135-1175","authenticated-orcid":false,"given":"Jean","family":"Popovici","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rithea","family":"Leang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"Ringwald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Ariey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3024-5928","authenticated-orcid":false,"given":"Romain","family":"Copp\u00e9e","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8599-6382","authenticated-orcid":false,"given":"Benoit","family":"Witkowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,27]]},"reference":[{"key":"65629_CR1","unstructured":"World Health Organization. World Malaria Report 2022 (2022)."},{"key":"65629_CR2","doi-asserted-by":"publisher","first-page":"1807","DOI":"10.1038\/d41591-024-00028-y","volume":"30","author":"DS Ishengoma","year":"2024","unstructured":"Ishengoma, D. S. et al. Urgent action is needed to confront artemisinin partial resistance in African malaria parasites. Nat. Med. 30, 1807\u20131808 (2024).","journal-title":"Nat. Med."},{"key":"65629_CR3","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1038\/nature12876","volume":"505","author":"F Ariey","year":"2014","unstructured":"Ariey, F. et al. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature 505, 50\u201355 (2014).","journal-title":"Nature"},{"key":"65629_CR4","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/S1473-3099(16)30415-7","volume":"17","author":"B Witkowski","year":"2017","unstructured":"Witkowski, B. et al. A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype-genotype association study.  Lancet Infect. Dis. 17, 174\u2013183 (2017).","journal-title":"Lancet Infect. Dis."},{"key":"65629_CR5","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/S1473-3099(15)00487-9","volume":"16","author":"C Amaratunga","year":"2016","unstructured":"Amaratunga, C. et al. Dihydroartemisinin\u2013piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study.  Lancet Infect. Dis. 16, 357\u2013365 (2016).","journal-title":"Lancet Infect. Dis."},{"key":"65629_CR6","doi-asserted-by":"crossref","unstructured":"Imwong, M. et al. The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong Subregion: a molecular epidemiology observational study. Lancet Infect. Dis. 17, 491\u2013497 (2017).","DOI":"10.1016\/S1473-3099(17)30048-8"},{"key":"65629_CR7","doi-asserted-by":"publisher","first-page":"4719","DOI":"10.1128\/AAC.00835-15","volume":"59","author":"R Leang","year":"2015","unstructured":"Leang, R. et al. Evidence of Plasmodium falciparum malaria multidrug resistance to artemisinin and piperaquine in western Cambodia: dihydroartemisinin-piperaquine open-label multicenter clinical assessment. Antimicrob. Agents Chemother. 59, 4719\u20134726 (2015).","journal-title":"Antimicrob. Agents Chemother."},{"key":"65629_CR8","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-9-273","volume":"9","author":"K Na-Bangchang","year":"2010","unstructured":"Na-Bangchang, K. et al. Declining in efficacy of a three-day combination regimen of mefloquine-artesunate in a multi-drug resistance area along the Thai-Myanmar border. Malar. J. 9, 273 (2010).","journal-title":"Malar. 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Arterolane\u2013piperaquine\u2013mefloquine versus arterolane\u2013piperaquine and artemether\u2013lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Kenyan children: a single-centre, open-label, randomised, non-inferiority trial.  Lancet Infect. Dis. 21, 1395\u20131406 (2021).","journal-title":"Lancet Infect. Dis."},{"key":"65629_CR12","doi-asserted-by":"publisher","first-page":"100966","DOI":"10.1016\/j.lanmic.2024.100966","volume":"6","author":"A Mahamar","year":"2025","unstructured":"Mahamar, A. et al. Artemether-lumefantrine-amodiaquine or artesunate-amodiaquine combined with single low-dose primaquine to reduce Plasmodium falciparum malaria transmission in Ou\u00e9less\u00e9bougou, Mali: a five-arm, phase 2, single-blind, randomised controlled trial. Lancet Microbe 6, 100966 (2025).","journal-title":"Lancet Microbe"},{"key":"65629_CR13","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1016\/S1473-3099(21)00692-7","volume":"22","author":"TJ Peto","year":"2022","unstructured":"Peto, T. J. et al. Triple therapy with artemether\u2013lumefantrine plus amodiaquine versus artemether\u2013lumefantrine alone for artemisinin-resistant, uncomplicated falciparum malaria: an open-label, randomised, multicentre trial.  Lancet Infect. Dis. 22, 867\u2013878 (2022).","journal-title":"Lancet Infect. Dis."},{"key":"65629_CR14","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1016\/S0140-6736(20)30552-3","volume":"395","author":"RW Van Der Pluijm","year":"2020","unstructured":"Van Der Pluijm, R. W. et al. Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial.  Lancet 395, 1345\u20131360 (2020).","journal-title":"Lancet"},{"key":"65629_CR15","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01121-21","volume":"65","author":"M Imwong","year":"2021","unstructured":"Imwong, M. et al. Evolution of multidrug resistance in Plasmodium falciparum: a longitudinal study of genetic resistance markers in the greater Mekong subregion. Antimicrob. Agents Chemother. 65, e01121-21 (2021).","journal-title":"Antimicrob. Agents Chemother."},{"key":"65629_CR16","doi-asserted-by":"crossref","unstructured":"Shirley, M. W. et al. Chromosome 9 from independent clones and isolates of Plasmodium falciparum undergoes subtelomeric deletions with similar breakpoints in vitro. Mol. Biochem. Parasitol. 40, 137\u2013145 (1990).","DOI":"10.1016\/0166-6851(90)90087-3"},{"key":"65629_CR17","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00060-19","volume":"63","author":"B Hanboonkunupakarn","year":"2019","unstructured":"Hanboonkunupakarn, B. et al. Sequential open-label study of the safety, tolerability, and pharmacokinetic interactions between dihydroartemisinin-piperaquine and mefloquine in healthy Thai adults. Antimicrob. Agents Chemother. 63, e00060-19 (2019).","journal-title":"Antimicrob. Agents Chemother."},{"key":"65629_CR18","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1016\/S1473-3099(17)30635-7","volume":"17","author":"G Rossi","year":"2017","unstructured":"Rossi, G. et al. Emergence of Plasmodium falciparum triple mutant in Cambodia.  Lancet Infect. Dis. 17, 1233 (2017).","journal-title":"Lancet Infect. Dis."},{"key":"65629_CR19","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1093\/jac\/dkac403","volume":"78","author":"M Mairet-Khedim","year":"2023","unstructured":"Mairet-Khedim, M. et al. Prevalence and characterization of piperaquine, mefloquine and artemisinin derivatives triple-resistant Plasmodium falciparum in Cambodia. J. Antimicrob. 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PLoS Biol. 20, e3001616 (2022).","journal-title":"PLoS Biol."},{"key":"65629_CR25","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1016\/S1473-3099(18)30068-9","volume":"18","author":"R Amato","year":"2018","unstructured":"Amato, R. et al. Origins of the current outbreak of multidrug-resistant malaria in southeast Asia: a retrospective genetic study.  Lancet Infect. Dis. 18, 337\u2013345 (2018).","journal-title":"Lancet Infect. Dis."},{"key":"65629_CR26","doi-asserted-by":"crossref","unstructured":"Beghain, J. et al. Plasmodium copy number variation scan: gene copy numbers evaluation in haploid genomes. Malar. J. 15, 206 (2016)","DOI":"10.1186\/s12936-016-1258-x"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-025-65629-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-025-65629-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-025-65629-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T13:55:15Z","timestamp":1764251715000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-025-65629-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,27]]},"references-count":26,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["65629"],"URL":"https:\/\/doi.org\/10.1038\/s41467-025-65629-8","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-6629488\/v1","asserted-by":"object"}]},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,27]]},"assertion":[{"value":"9 May 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The funders had no role in the study design, data collection and interpretation, or in the decision to submit the work for publication. None of the authors declared a financial conflict of interest. P.R. is a staff member of the World Health Organization. The authors are solely responsible for the views expressed in this publication, which do not necessarily represent the decisions, policies, or views of the World Health Organization.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"10634"}}