{
  "abstract": "Artemisinin-based combination therapies are the cornerstone of malaria treatment and control. In Africa, artemether-lumefantrine is the most widely used first-line artemisinin-based combination therapy, but its efficacy in Uganda is increasingly threatened by the emergence of artemisinin partial resistance and reduced lumefantrine susceptibility. To identify loci contributing to this decreased susceptibility, here we assessed signatures of selection in 157 whole-genome sequences of Plasmodium falciparum from Uganda. Although extended haplotypes were observed around Kelch13 C469Y and A675V mutations, the strongest signal of recent selection was centered on a segment of chr. 7 encoding the phosphoinositide-binding protein (PX1, PF3D7_0720700). A haplotype, represented by three PX1 mutations (L1222P, M1701I and D1705N) and two deletions (designated PIN), was first seen in 2008 and rapidly increased, reaching a prevalence >50% in northern Uganda by 2016 and eastern Uganda by 2023. PIN-carrying parasites showed significantly decreased ex vivo susceptibilities to lumefantrine, mefloquine and dihydroartemisinin, an active metabolite of artemether. A parasite strain in which px1 was disrupted in vitro showed increased susceptibility to the three drugs. Thus, PX1 polymorphisms appear to impact on the susceptibilities of African malaria parasites to key drugs.",
  "abstract_shown": true,
  "affiliations": [
    "Center for Computational Molecular Biology, Brown University, Providence, RI, USA. karamoko_niare@brown.edu",
    "Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA. karamoko_niare@brown.edu",
    "Department of Medicine, University of California, San Francisco, San Francisco, CA, USA",
    "Institute for Global Health and Infectious Diseases, University of North Carolina, Chapel Hill, NC, USA",
    "Infectious Diseases Research Collaboration, Kampala, Uganda",
    "Institute for Tropical Medicine, University of Tubingen, Tubingen, Germany",
    "Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA",
    "Department of Disease Control and Environmental Health, Makerere University, Kampala, Uganda",
    "Department of Microbiology-Infectious Diseases and Immunology, Université Laval, Quebec, Quebec, Canada",
    "Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN, USA",
    "Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA",
    "Division of Infectious Diseases, School of Medicine, University of North Carolina, Chapel Hill, NC, USA",
    "Center for Computational Molecular Biology, Brown University, Providence, RI, USA",
    "Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. mconrad6@jh.edu",
    "Johns Hopkins Malaria Research Institute, Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. mconrad6@jh.edu"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 19,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Karamoko Niaré",
      "orcid": "0000-0002-7406-9508"
    },
    {
      "affs": [
        2
      ],
      "name": "Bersabeh D. Tafesse",
      "orcid": "0009-0002-4301-8764"
    },
    {
      "affs": [
        2
      ],
      "name": "Mayland Treat"
    },
    {
      "affs": [
        3
      ],
      "name": "Jacob M. Sadler",
      "orcid": "0009-0001-6430-608X"
    },
    {
      "affs": [
        4
      ],
      "name": "Martin Okitwi",
      "orcid": "0000-0003-2712-2174"
    },
    {
      "affs": [
        4
      ],
      "name": "Stephen Orena"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Victor Asua",
      "orcid": "0000-0002-0489-4692"
    },
    {
      "affs": [
        2
      ],
      "name": "Oriana Kreutzfeld",
      "orcid": "0000-0003-2026-345X"
    },
    {
      "affs": [
        2
      ],
      "name": "Jenny Legac"
    },
    {
      "affs": [
        6
      ],
      "name": "Jacob Marglous",
      "orcid": "0000-0002-3592-1382"
    },
    {
      "affs": [
        4
      ],
      "name": "Samuel L. Nsobya",
      "orcid": "0000-0003-4986-8823"
    },
    {
      "affs": [
        7,
        4
      ],
      "name": "Adoke Yeka",
      "orcid": "0000-0002-2899-1470"
    },
    {
      "affs": [
        8
      ],
      "name": "Dave Richard",
      "orcid": "0000-0003-2269-6240"
    },
    {
      "affs": [
        9
      ],
      "name": "Michael T. Ferdig",
      "orcid": "0000-0003-3516-9829"
    },
    {
      "affs": [
        9
      ],
      "name": "Angana Mukherjee",
      "orcid": "0000-0002-7080-494X"
    },
    {
      "affs": [
        2
      ],
      "name": "Philip Jon Rosenthal",
      "orcid": "0000-0002-7953-7622"
    },
    {
      "affs": [
        10,
        11,
        3
      ],
      "name": "Jonathan J. Juliano",
      "orcid": "0000-0002-0591-0850"
    },
    {
      "affs": [
        12,
        6
      ],
      "name": "Jeffrey A. Bailey",
      "orcid": "0000-0002-6899-8204"
    },
    {
      "affs": [
        13,
        14
      ],
      "name": "Melissa D. Conrad",
      "orcid": "0000-0002-9984-8030"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4pcbf57d3nfpn.bib",
  "cited_by": 19,
  "doi": "10.1038/s41591-026-04590-5",
  "fulltext_url": null,
  "id": "4pcbf57d3nfpn",
  "issns": [
    "1078-8956",
    "1546-170X",
    "1744-7933"
  ],
  "landing_url": "https://doi.org/10.1038/s41591-026-04590-5",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2739|Malaria Research and Control"
    ]
  ],
  "openalex": "W7203627860",
  "pdf_url": null,
  "pmcid": "PMC12324449",
  "pmid": "40766679",
  "published": "2026-08-17",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/4pcbf57d3nfpn.ris",
  "sources": [
    {
      "first_seen": "2026-11-05T13:21:05Z",
      "native_id": "W7203627860",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41591-026-04590-5"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2739|Malaria Research and Control",
      "subfield": "epidemiology-public-health"
    }
  ],
  "title": "Emergence and spread of Plasmodium falciparum PX1 polymorphisms associated with decreased susceptibility to antimalarials in Uganda",
  "title_text": "Emergence and spread of Plasmodium falciparum PX1 polymorphisms associated with decreased susceptibility to antimalarials in Uganda",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T13:20:50Z",
  "url": "https://research.draconitic.com/paper/4pcbf57d3nfpn",
  "venue": "Nature Medicine",
  "versions": []
}