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Antimicrobial Agents and Chemotherapy, February 2003, p. 709-718, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.709-718.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Genetics of Mefloquine Resistance in the Rodent Malaria Parasite Plasmodium chabaudi

Pedro V. L. Cravo,1,2 Jane M.-R. Carlton,3 Paul Hunt,1 Laura Bisoni,4 Rose Ann Padua,5 and David Walliker1*

Institute of Cell, Animal, and Population Biology, University of Edinburgh, Edinburgh EH9 3JT,1 Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, Scotland,4 Department of Haematological Medicine, King's College Hospital, London SE5 9NU, United Kingdom,5 Centro de Malária e Outras Doenças Tropicais/IHMT, 1349-008 Lisbon, Portugal,2 The Institute for Genomic Research, Rockville, Maryland 208503

Received 9 September 2002/ Returned for modification 15 October 2002/ Accepted 14 November 2002

The genetic determinants of resistance to mefloquine in malaria parasites are unclear. Some studies have implied that amplification of, or mutations in, the multidrug resistance gene pfmdr1 in Plasmodium falciparum may be involved. Using the rodent malaria model Plasmodium chabaudi, we investigated the role of the orthologue of this gene, pcmdr1, in a stable mefloquine-resistant mutant, AS(15MF/3), selected from a sensitive clone. pcmdr1 exists as a single copy gene on chromosome 12 of the sensitive clone. In AS(15MF/3), the gene was found to have undergone duplication, with one copy translocating to chromosome 4. mRNA levels of pcmdr1 were higher in the mutant than in the parent sensitive clone. A partial genetic map of the translocation showed that other genes in addition to pcmdr1 had been cotranslocated. The sequences of both copies of pcmdr1 of AS(15MF/3) were identical to that of the parent sensitive clone. A cross was made between AS(15MF/3) and an unrelated mefloquine-sensitive clone, AJ. Phenotypic and molecular analysis of progeny clones showed that duplication and overexpression of the pcmdr1 gene was an important determinant of resistance. However, not all mefloquine-resistant progeny contained the duplicated gene, showing that at least one other gene was involved in resistance.

* Corresponding author. Mailing address: Institute of Cell, Animal and Population Biology, University of Edinburgh, Ashworth Laboratories, West Mains Road, Edinburgh EH9 3JT, United Kingdom. Phone: (44) 131-650-5548. Fax: (44) 131-667-6564. E-mail: D.Walliker{at}ed.ac.uk.

Antimicrobial Agents and Chemotherapy, February 2003, p. 709-718, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.709-718.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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