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Antimicrobial Agents and Chemotherapy, December 1999, p. 2943-2949, Vol. 43, No. 12
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

The pfmdr1 Gene Is Associated with a Multidrug-Resistant Phenotype in Plasmodium falciparum from the Western Border of Thailand

R. N. Price,1,2,3 C. Cassar,1 A. Brockman,2,4 M. Duraisingh,5 M. van Vugt,2,4,6 N. J. White,3,4 F. Nosten,2,3,4 and S. Krishna1,*

Department of Infectious Diseases, St. George's Hospital Medical School,1 and Department of Medical Parasitology and Clinical Sciences, London School of Hygiene and Tropical Medicine,5 London, and Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford,3 United Kingdom; Shoklo Malaria Research Unit, Mae Sod, Tak Province,2 and Faculty of Tropical Medicine, Mahidol University, Bangkok,4 Thailand; and Department of Infectious Diseases, Tropical Medicine and AIDS, Amsterdam Medical Center, Amsterdam, The Netherlands6

Received 24 May 1999/Returned for modification 12 July 1999/Accepted 4 October 1999

On the western border of Thailand, Plasmodium falciparum has become resistant to almost all antimalarial agents. The molecular basis of resistance in these parasite populations has not been well characterized. This study assessed genetic polymorphisms in the pfmdr1 gene in 54 parasites collected from the western border of Thailand to determine the relationship of pfmdr1 copy number and codon mutations with parasite sensitivities to mefloquine, chloroquine, halofantrine, quinine, and artesunate assessed in vitro. A point mutation at codon 86 (resulting in a change of Asn to Tyr) was associated with a significantly lower 50% inhibitory concentration (IC50) of mefloquine (median, 9 ng/ml versus 52.4 ng/ml; P = 0.003). Overall 35% of the isolates (19 of 54) had an increase in pfmdr1 copy number, and all 19 carried the wild-type allele at codon 86. Increased pfmdr1 copy number was associated with higher IC50s of mefloquine (P = 0.04) and artesunate (P = 0.005), independent of polymorphism at codon 86. The relationship between pfmdr1 and resistance to structurally distinct antimalarial agents confirms the presence of a true multidrug-resistant phenotype.

* Corresponding author. Mailing address: Department of Infectious Diseases, St. George's Hospital Medical School, London SW17, United Kingdom. Phone: (44) 181 725 5836. Fax: (44) 181 725 3487. E-mail: s.krishna{at}sghms.ac.uk.

Antimicrobial Agents and Chemotherapy, December 1999, p. 2943-2949, Vol. 43, No. 12
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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