Changes in susceptibility of Plasmodium falciparum to antimalarial drugs in Uganda over time: 2019–2024
Abstract The treatment and control of malaria in Africa is challenged by drug resistance. We characterized ex vivo susceptibilities to nine drugs of isolates collected from individuals presenting with uncomplicated falciparum malaria in eastern (2019-2024) and northern (2021-2024) Uganda and perform...
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62810-x |
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| author | Martin Okitwi Stephen Orena Patrick K. Tumwebaze Thomas Katairo Yoweri Taremwa Oswald Byaruhanga Stephen Tukwasibwe Samuel L. Nsobya Jennifer Legac Jeffrey A. Bailey Roland A. Cooper Melissa D. Conrad Philip J. Rosenthal |
| author_facet | Martin Okitwi Stephen Orena Patrick K. Tumwebaze Thomas Katairo Yoweri Taremwa Oswald Byaruhanga Stephen Tukwasibwe Samuel L. Nsobya Jennifer Legac Jeffrey A. Bailey Roland A. Cooper Melissa D. Conrad Philip J. Rosenthal |
| author_sort | Martin Okitwi |
| collection | DOAJ |
| description | Abstract The treatment and control of malaria in Africa is challenged by drug resistance. We characterized ex vivo susceptibilities to nine drugs of isolates collected from individuals presenting with uncomplicated falciparum malaria in eastern (2019-2024) and northern (2021-2024) Uganda and performed deep sequencing, with analysis of 80 Plasmodium falciparum genes, to evaluate associations between susceptibilities and potential resistance markers for samples studied since 2016. For 1114 evaluated isolates, median half-maximal inhibitory concentrations (IC50s) were low-nanomolar for chloroquine, monodesethylamodiaquine, piperaquine, pyronaridine, lumefantrine, mefloquine, and DHA, but higher for quinine and pyrimethamine. Over time, susceptibilities improved for chloroquine, decreased for lumefantrine, mefloquine, and DHA, and were unchanged for other drugs. Changes in prevalences of known markers of altered drug susceptibility followed the same patterns. Genotypes associated with drug susceptibility were those previously identified for aminoquinolines and pyrimethamine. For lumefantrine, susceptibility was decreased with wild-type PfCRT K76T or PfMDR1 N86Y, mutant PfK13 C469Y or A675V, mutant PfCARL D611N, and other polymorphisms. For DHA, susceptibility was decreased with the PfK13 C469Y or A675V and PfMDR1 Y500N mutations. Decreasing activities of lumefantrine and DHA suggest potential loss of efficacies of leading regimens, although the clinical consequences of these changes are, to date, uncertain. |
| format | Article |
| id | doaj-art-b0a126b38cce4f89a62ad73ef848d6cf |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b0a126b38cce4f89a62ad73ef848d6cf2025-08-20T03:42:55ZengNature PortfolioNature Communications2041-17232025-08-011611910.1038/s41467-025-62810-xChanges in susceptibility of Plasmodium falciparum to antimalarial drugs in Uganda over time: 2019–2024Martin Okitwi0Stephen Orena1Patrick K. Tumwebaze2Thomas Katairo3Yoweri Taremwa4Oswald Byaruhanga5Stephen Tukwasibwe6Samuel L. Nsobya7Jennifer Legac8Jeffrey A. Bailey9Roland A. Cooper10Melissa D. Conrad11Philip J. Rosenthal12Infectious Diseases Research CollaborationInfectious Diseases Research CollaborationInfectious Diseases Research CollaborationInfectious Diseases Research CollaborationInfectious Diseases Research CollaborationInfectious Diseases Research CollaborationInfectious Diseases Research CollaborationInfectious Diseases Research CollaborationDepartment of Medicine, University of CaliforniaBrown UniversityDepartment of Natural Sciences and Mathematics, Dominican University of CaliforniaDepartment of Medicine, University of CaliforniaDepartment of Medicine, University of CaliforniaAbstract The treatment and control of malaria in Africa is challenged by drug resistance. We characterized ex vivo susceptibilities to nine drugs of isolates collected from individuals presenting with uncomplicated falciparum malaria in eastern (2019-2024) and northern (2021-2024) Uganda and performed deep sequencing, with analysis of 80 Plasmodium falciparum genes, to evaluate associations between susceptibilities and potential resistance markers for samples studied since 2016. For 1114 evaluated isolates, median half-maximal inhibitory concentrations (IC50s) were low-nanomolar for chloroquine, monodesethylamodiaquine, piperaquine, pyronaridine, lumefantrine, mefloquine, and DHA, but higher for quinine and pyrimethamine. Over time, susceptibilities improved for chloroquine, decreased for lumefantrine, mefloquine, and DHA, and were unchanged for other drugs. Changes in prevalences of known markers of altered drug susceptibility followed the same patterns. Genotypes associated with drug susceptibility were those previously identified for aminoquinolines and pyrimethamine. For lumefantrine, susceptibility was decreased with wild-type PfCRT K76T or PfMDR1 N86Y, mutant PfK13 C469Y or A675V, mutant PfCARL D611N, and other polymorphisms. For DHA, susceptibility was decreased with the PfK13 C469Y or A675V and PfMDR1 Y500N mutations. Decreasing activities of lumefantrine and DHA suggest potential loss of efficacies of leading regimens, although the clinical consequences of these changes are, to date, uncertain.https://doi.org/10.1038/s41467-025-62810-x |
| spellingShingle | Martin Okitwi Stephen Orena Patrick K. Tumwebaze Thomas Katairo Yoweri Taremwa Oswald Byaruhanga Stephen Tukwasibwe Samuel L. Nsobya Jennifer Legac Jeffrey A. Bailey Roland A. Cooper Melissa D. Conrad Philip J. Rosenthal Changes in susceptibility of Plasmodium falciparum to antimalarial drugs in Uganda over time: 2019–2024 Nature Communications |
| title | Changes in susceptibility of Plasmodium falciparum to antimalarial drugs in Uganda over time: 2019–2024 |
| title_full | Changes in susceptibility of Plasmodium falciparum to antimalarial drugs in Uganda over time: 2019–2024 |
| title_fullStr | Changes in susceptibility of Plasmodium falciparum to antimalarial drugs in Uganda over time: 2019–2024 |
| title_full_unstemmed | Changes in susceptibility of Plasmodium falciparum to antimalarial drugs in Uganda over time: 2019–2024 |
| title_short | Changes in susceptibility of Plasmodium falciparum to antimalarial drugs in Uganda over time: 2019–2024 |
| title_sort | changes in susceptibility of plasmodium falciparum to antimalarial drugs in uganda over time 2019 2024 |
| url | https://doi.org/10.1038/s41467-025-62810-x |
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