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Antimicrobial Agents and Chemotherapy, April 2009, p. 1509-1515, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.00241-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Plasmodium falciparum pfmdr1 Amplification, Mefloquine Resistance, and Parasite Fitness{triangledown} ,{dagger}

Piyanuch Preechapornkul,1 Mallika Imwong,1 Kesinee Chotivanich,1 Wirichada Pongtavornpinyo,1 Arjen M. Dondorp,1,2 Nicholas P. J. Day,1,2 Nicholas J. White,1,2* and Sasithon Pukrittayakamee1

Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand,1 Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, United Kingdom2

Received 21 February 2008/ Returned for modification 1 April 2008/ Accepted 8 January 2009

Mefloquine is widely used in combination with artemisinin derivatives for the treatment of falciparum malaria. Mefloquine resistance in Plasmodium falciparum has been related to increased copy numbers of multidrug-resistant gene 1 (pfmdr1). We studied the ex vivo dynamics of pfmdr1 gene amplification in culture-adapted P. falciparum in relation to mefloquine resistance and parasite fitness. A Thai P. falciparum isolate (isolate TM036) was assessed by the use of multiple genetic markers as a single genotype. Resistance was selected by exposure to stepwise increasing concentrations of mefloquine up to 30 ng/ml in continuous culture. The pfmdr1 gene copy numbers increased as susceptibility to mefloquine declined (P = 0.03). No codon mutations at positions 86, 184, 1034, 1042, and 1246 in the pfmdr1 gene were detected. Two subclones of selected parasites (average copy numbers, 2.3 and 3.1, respectively) showed a fitness disadvantage when they were grown together with the original parasites containing a single pfmdr1 gene copy in the absence of mefloquine; the multiplication rates were 6.3% and 8.7% lower, respectively (P < 0.01). Modeling of the dynamics of the pfmdr1 copy numbers over time in relation to the relative fitness of the parasites suggested that net pfmdr1 gene amplification from one to two copies occurs once in every 108 parasites and that amplification from two to three copies occurs once in every 103 parasites. pfmdr1 gene amplification in P. falciparum is a frequent event and confers mefloquine resistance. Parasites with multiple copies of the pfmdr1 gene have decreased survival fitness in the absence of drug pressure.

* Corresponding author. Mailing address: Mahidol-Oxford Tropical Medicine Research Unit, 420/6 Rajvithi Rd., Bangkok 10400, Thailand. Phone: (662) 203-6333. Fax: (662) 354-9169. E-mail: nickw{at}tropmedres.ac

{triangledown} Published ahead of print on 21 January 2009.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, April 2009, p. 1509-1515, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.00241-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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