A Strong Association between Mefloquine and Halofantrine Resistance and Amplification, Overexpression, and Mutation in the P-Glycoprotein Gene Homolog (pfmdr) of Plasmodium falciparum In Vitro

Sheila A. Peel Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

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Patricia Bright Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

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Boyd Yount Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

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Jean Handy Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

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Ralph S. Baric Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

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DOI:
https://doi.org/10.4269/ajtmh.1994.51.648
Volume/Issue:
Volume 51: Issue 5
Page(s):
648–658
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Stepwise selection for increased mefloquine resistance in a line of Plasmodium falciparum in vitro resulted in increased resistance to halofantrine and quinine, increased sensitivity to chloroquine, and amplification and overexpression of the P-glycoprotein gene homolog (pfmdr1). A point mutation (tyrosine to phenylalanine) noted at amino acid 86 in pfmdr1 in the mefloquine-resistant line W2mef was amplified in more resistant lines derived from it by in vitro selection pressure with mefloquine. Conversely, lines selected for increased chloroquine resistance exhibited a revertant phenotype that was sensitive to mefloquine and halofantrine. These lines also demonstrated increased sensitivity to quinine, loss of amplification of pfmdr1, loss of the mefloquine/halofantrine phenylalanine-86 mutation, and selection for a tyrosine-86 mutation previously associated with chloroquine resistance. These findings provide strong evidence for pfmdr1 mediating cross-resistance to halofantrine and mefloquine in P. falciparum in vitro.
Copyright:
Copyright © 1994 by The American Society of Tropical Medicine and Hygiene 1994
Published Online:
Nov 1994
Cover The American Journal of Tropical Medicine and Hygiene
The American Journal of Tropical Medicine and Hygiene
Print ISSN:
0002-9637
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