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Chloroquine resistance not linked to mdr-like genes in a Plasmodium falciparum cross

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Abstract

CHLOROQUINE is thought to act against falciparum malaria by accumulating in the acid vesicles of the parasite and interfering with their function1–4. Parasites resistant to chloroquine expel the drug rapidly in an unaltered form, thereby reducing levels of accumulation in the vesicles5. The discovery that verapamil partially reverses chloroquine resistance in vitro6 led to the proposal that efflux may involve an ATP-driven P-glycoprotein pump similar to that in mammalian multidrug-resistant (mdr) tumor cell lines. Indeed, Plasmodium falciparum contains at least two mdr-like genes7,8, one of which has been suggested to confer the chloroquine resistant (CQR) phenotype7,9,10. To determine if either of these genes is linked to chloroquine resistance, we performed a genetic cross between CQR and chloroquine-susceptible (CQS) clones of P. falciparum. Examination of 16 independent recombinant progeny indicated that the rapid efflux phenotype is controlled by a single gene or a closely linked group of genes. But, there was no linkage between the rapid efflux, CQR phenotype and either of the mdr-like P. falciparum genes or amplification of those genes. These data indicate that the genetic locus governing chloroquine efflux and resistance is independent of the known mdr-like genes.

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Author notes

  1. Lindsey J. Panton

    Present address: Departments of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, 02115, USA

  2. Virgilio E. do Rosario

    Present address: Genetics Department, Edinburgh University, Edinburgh, EH9 3JN, UK

Authors and Affiliations

  1. Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, 20892, USA

    Thomas E. Wellems, Robert W. Gwadz & Annie Walker-Jonah

  2. Departments of Medicine and Pathology, Washington University School of Medicine, St Louis, Missouri, 63110, USA

    Ilya Y. Gluzman & Donald J. Krogstad

Authors
  1. Thomas E. Wellems
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  2. Lindsey J. Panton
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  3. Ilya Y. Gluzman
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  4. Virgilio E. do Rosario
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  5. Robert W. Gwadz
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  6. Annie Walker-Jonah
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  7. Donald J. Krogstad
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Wellems, T., Panton, L., Gluzman, I. et al. Chloroquine resistance not linked to mdr-like genes in a Plasmodium falciparum cross. Nature 345, 253–255 (1990). https://doi.org/10.1038/345253a0

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