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Am. J. Trop. Med. Hyg., 81(2), 2009, pp. 348-355
Copyright © 2009 by The American Society of Tropical Medicine and Hygiene

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Assessment of the Origins and Spread of Putative Resistance-Conferring Mutations in Plasmodium vivax Dihydropteroate Synthase

Vivian N. Hawkins, Stephanie M. Suzuki, Kanchana Rungsihirunrat, Hapuarachchige C. Hapuarachchi, Amanda Maestre, Kesara Na-Bangchang, AND Carol Hopkins Sibley*
Department of Genome Sciences, University of Washington, Seattle, Washington; College of Public Health Sciences, Chulalongkorn University, Bangkok, Thailand; Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka; Grupo Salud y Comunidad, Universidad de Antioquia, Medellín, Colombia; Faculty of Allied Health Sciences, Thammasat University, Pathumthanee, Thailand

Infection with Plasmodium vivax is usually treated with chloroquine, but parasites are often exposed inadvertently to sulfadoxine-pyrimethamine. To infer patterns of selection and spread of resistant parasites in natural populations, we determined haplotypes of P. vivax dihydropteroate synthase (dhps) alleles that could confer resistance to sulfadoxine. We amplified the P. vivax pyrophosphokinase (pppk)–dhps region and its flanking intergenic regions from 92 contemporary global isolates. Introns and exons of pppk-dhps were highly polymorphic, as were the flanking intergenic regions. Eighteen haplotypes were associated with wild-type alleles, but several different putatively sulfadoxine-resistant alleles have arisen in areas of intensive sulfadoxine-pyrimethamine use. Even when they encoded changes to the same amino acid, these mutant alleles were associated with multiple different haplotypes. Two main conclusions can be drawn from these data. First, dhps alleles resistant to sulfadoxine have arisen multiple times under drug pressure. Second, there has been convergent evolution of a variety of alleles that could confer resistance to sulfa drugs.

Received October 11, 2008. Accepted for publication May 20, 2009.

Acknowledgments: Vivian H. Hawkins and Carol Hopkins Sibley thank Marnie R. Briceno, Berenger A. A. Ako, Marie-Solange Evehe, and Joseph D. Smith for critical review of the manuscript.

Financial support: This study was supported by grant AI 55604 from the National Institutes of Health to Carol Hopkins Sibley. Kanchana Rungsihirunrat was supported by a Golden Jubilee Scholarship.

* Address correspondence to Carol Hopkins Sibley, Department of Genome Science, University of Washington, Seattle, WA 98195-5065. E-mail: sibley{at}u.washington.edu

Authors’ addresses: Vivian N. Hawkins, Stephanie M. Suzuki, and Carol Hopkins Sibley, Department of Genome Sciences, University of Washington, Seattle, WA 98195-5065. Kanchana Rungsihirunrat, College of Public Health Sciences, Chulalongkorn University, Bangkok Thailand and Faculty of Allied Health Sciences, Thammasat University, Pathumthanee Thailand. Hapuarachchige C. Hapuarachchi, Faculty of Medicine, University of Kelaniya, Ragama Sri Lanka. Amanda Maestre, Grupo Salud y Comunidad, Universidad de Antioquia, Medellín Colombia. Kesara Na-Bangchang, Faculty of Allied Health Sciences, Thammasat University, Pathumthanee Thailand.






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