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POINT MUTATIONS IN THE DIHYDROFOLATE REDUCTASE AND DIHYDROPTEROATE SYNTHASE GENES OF PLASMODIUM FALCIPARUM AND RESISTANCE TO SULFADOXINE-PYRIMETHAMINE IN SRI LANKA

Sulfadoxine-pyrimethamine (SP) is the second-line treatment for Plasmodium falciparum malaria in Sri Lanka. Resistance to SP is caused by point mutations in the dihydrofolate reductase (Pf-dhfr) and dihydropteroate synthase (Pf-dhps) genes of P. falciparum. We determined the genotype of Pf-dhfr and Pf-dhps and the clinical response to SP in 30 field isolates of P. falciparum from Sri Lanka. All patients treated with SP had an adequate clinical response. Eighty-five percent (23 of 27) of pure field isolates carried parasites with double mutant alleles of Pf-dhfr (C59R + S108N) and showed about 200-fold higher levels of resistance to pyrimethamine than the wild type in a yeast system. None of the isolates had either known or novel mutations at other positions in the dhfr domain. In contrast, 67% (20 of 30) of the isolates carried parasites that were wild type for Pf-dhps. In Sri Lanka, detection of the triple mutant allele of Pf-dhfr will require tracking mutations at codon 51.

Received March 24, 2005. Accepted for publication October 6, 2005.

Acknowledgments: We thank the Police Department staff at Sector 8 Base Camp, the First Battalion of the Sri Lanka Light Infantry at the Pulliadirakkam Base Camp, and the registered medical officer and the Deputy Provincial Director of Health Services, Vavuniya for assisting us in the field.

Financial support: This study was supported by the National Science Foundation, Sri Lanka, the International Atomic Energy Agency, the and National Institutes of Health through research grants SIDA/2001/BT/01, SL6/028, and NIH AI-55604 respectively.

^* Address correspondence to Carol Hopkins Sibley, Department of Genome Sciences, Box 357730, University of Washington, Seattle, WA 98195-7730. E-mail: sibley{at}gs.washington.edu

Authors’ addresses: Hapuarachchige C. Hapuarachchi, Meegoda Y. D. Dayanath, Kandeyaye Bandaralage A. T. Bandara, Sudusinghe Abeysundara, Wimaladharma Abeyewickreme and Nilanthi R de Silva, Department of Parasitology, Faculty of Medicine, University of Kelaniya, P.O. Box 6, Thalagolla Road, Ragama, Sri Lanka, Telephone: 94-11-295-3412, Fax: 94-11-295-3412. Sonia Y. Hunt and Carol Hopkins Sibley, Department of Genome Sciences, Box 357730, University of Washington, Seattle, WA 98195-7730, Telephone: 206-685-9378, Fax: 206-543-0754, E-mail: sibley{at}gs.washington.edu.

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