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Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum

Nature volume 403, pages 906–909 (2000)Cite this article

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.

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Figure 1: Allelic replacement of the pfmdr1 gene.
Figure 2: Effect of introduction/removal of the polymorphisms in the D10 and 7G8 cloned lines on susceptibility and resistance to chloroquine, mefloquine, halofantrine, quinine and artemisinin.
Figure 3: Effect of pfmdr1 mutations on accumulation of antimalarials and modulation with verapamil.

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Acknowledgements

We thank S. Ward and P. Bray for the gift of [3H]chloroquine and for advice throughout this work, and T. Wellems and D. Fidock for providing the human dhfr gene. This work was supported by the National Health and Medical Research Council of Australia (NHMRC) and the National Institute of Health, USA. M.B.R. is supported by a NHMRC Peter Doherty Research Fellowship. We are grateful to the Blood Banks of the Red Cross of Victoria and Australian Capital Territory for generously providing serum and red cells.

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Authors and Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3050 , Victoria, Australia

    Michael B. Reed, Sonia R. Caruana & Alan F. Cowman

  2. Division of Biochemistry and Molecular Biology, Faculty of Science, Australian National University, 0200, Canberra , Australia

    Kevin J. Saliba & Kiaran Kirk

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Correspondence to Alan F. Cowman.

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Reed, M., Saliba, K., Caruana, S. et al. Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature 403, 906–909 (2000). https://doi.org/10.1038/35002615

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