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Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum

Author

Listed:
  • Michael B. Reed

    (The Walter and Eliza Hall Institute of Medical Research)

  • Kevin J. Saliba

    (Faculty of Science, Australian National University)

  • Sonia R. Caruana

    (The Walter and Eliza Hall Institute of Medical Research)

  • Kiaran Kirk

    (Faculty of Science, Australian National University)

  • Alan F. Cowman

    (The Walter and Eliza Hall Institute of Medical Research)

Abstract

Throughout the latter half of this century, the development and spread of resistance to most front-line antimalarial compounds used in the prevention and treatment of the most severe form of human malaria has given cause for grave clinical concern. Polymorphisms in pfmdr1, the gene encoding the P-glycoprotein homologue 1 (Pgh1) protein of Plasmodium falciparum, have been linked to chloroquine resistance1; Pgh1 has also been implicated in resistance to mefloquine and halofantrine2,3,4,5. However, conclusive evidence of a direct causal association between pfmdr1 and resistance to these antimalarials has remained elusive, and a single genetic cross has suggested that Pgh1 is not involved in resistance to chloroquine and mefloquine6. Here we provide direct proof that mutations in Pgh1 can confer resistance to mefloquine, quinine and halofantrine. The same mutations influence parasite resistance towards chloroquine in a strain-specific manner and the level of sensitivity to the structurally unrelated compound, artemisinin. This has important implications for the development and efficacy of future antimalarial agents.

Suggested Citation

  • Michael B. Reed & Kevin J. Saliba & Sonia R. Caruana & Kiaran Kirk & Alan F. Cowman, 2000. "Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum," Nature, Nature, vol. 403(6772), pages 906-909, February.
    • Handle: RePEc:nat:nature:v:403:y:2000:i:6772:d:10.1038_35002615
    DOI: 10.1038/35002615
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    Cited by:

    1. Ruixue Xu & Lirong Lin & Zhiwei Jiao & Rui Liang & Yazhen Guo & Yixin Zhang & Xiaoxu Shang & Yuezhou Wang & Xu Wang & Luming Yao & Shengfa Liu & Xianming Deng & Jing Yuan & Xin-zhuan Su & Jian Li, 2024. "Deaggregation of mutant Plasmodium yoelii de-ubiquitinase UBP1 alters MDR1 localization to confer multidrug resistance," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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