This Article Full Text Full Text (PDF) Supplemental material Other Versions of this Article: AAC.01228-06v1 51/6/2085    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McCollum, A. M. Articles by Escalante, A. A. Search for Related Content PubMed PubMed Citation Articles by McCollum, A. M. Articles by Escalante, A. A.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, June 2007, p. 2085-2091, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.01228-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Common Origin and Fixation of Plasmodium falciparum dhfr and dhps Mutations Associated with Sulfadoxine-Pyrimethamine Resistance in a Low-Transmission Area in South America ^,

Andrea M. McCollum,^1,2,3, Kristen Mueller,^2,4, Leopoldo Villegas,⁵ Venkatachalam Udhayakumar,² and Ananias A. Escalante^6*

Emory University, Program in Population Biology, Ecology, and Evolution, Atlanta, Georgia,¹ Malaria Branch, Division of Parasitic Diseases, National Center for Zoonotic, Vector-Borne, and Enteric Diseases, Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia,² Atlanta Research and Education Foundation, Atlanta, Georgia,³ Association of Public Health Laboratories, Washington, DC,⁴ Asociación Civil Impacto Social, Tumeremo, Venezuela,⁵ Arizona State University, School of Life Sciences, Tempe, Arizona⁶

Received 29 September 2006/ Returned for modification 9 November 2006/ Accepted 23 January 2007

Recent studies indicated that sensitive parasites could increase in frequency in a population when drugs are removed, suggesting that the life span of affordable antimalarial drugs could be expanded. We studied 97 samples from Bolivar State, Venezuela, an area where sulfadoxine-pyrimethamine (SP) has not been used for 8 years due to its ineffectiveness. We characterized point mutations in two genes that have been implicated in resistance to SP, dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps). We also assayed neutral microsatellite markers around the dhfr (chromosome 4) and dhps (chromosome 8) genes and on chromosomes 2 and 3 to track the origin and spread of resistant alleles. We found that drug-resistant SP mutants are fixed in the population. Two genotypes were present in the samples, dhfr(50R/51I/108N) dhps(437G/540E/581G) (90.7%) and dhfr(51I/108N) dhps(437G/581G) (9.3%). We show a single microsatellite haplotype for all of the dhfr and dhps alleles, and the alleles at the microsatellite loci are different from those present in Africa. Thus, in these samples from Venezuela, there is a single origin for both dhfr and dhps SP-resistant alleles, and these alleles originated independently of those characterized from Africa. Furthermore, this is the first report of a "hitchhiking effect" on the genetic variation around dhps due to selection by SP using an extensive set of microsatellite markers. Our results indicate that, in areas where there is limited gene flow, the fixation of drug-resistant parasites in the population is stable, even after drug selection is relaxed.

Published ahead of print on 5 February 2007.

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

A.M.M. and K.M. were equal contributors to this study.

This article has been cited by other articles:

• Zhou, Z., Griffing, S. M., de Oliveira, A. M., McCollum, A. M., Quezada, W. M., Arrospide, N., Escalante, A. A., Udhayakumar, V. (2008). Decline in Sulfadoxine-Pyrimethamine-Resistant Alleles after Change in Drug Policy in the Amazon Region of Peru. Antimicrob. Agents Chemother. 52: 739-741 [Abstract] [Full Text]