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Antimicrobial Agents and Chemotherapy, March 2007, p. 1071-1077, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.01186-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Independent Evolution of Pyrimethamine Resistance in Plasmodium falciparum Isolates in Melanesia{triangledown}

Toshihiro Mita,1* Kazuyuki Tanabe,2 Nobuyuki Takahashi,1 Takahiro Tsukahara,1 Hideaki Eto,1 Lek Dysoley,1,3 Hiroshi Ohmae,4 Kiyoshi Kita,5 Srivicha Krudsood,6 Sornchai Looareesuwan,6 Akira Kaneko,7 Anders Björkman,7 and Takatoshi Kobayakawa1

Department of International Affairs and Tropical Medicine, Tokyo Women's Medical University, Tokyo, Japan,1 Laboratory of Malariology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan,2 The National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia,3 Department of Parasitology, National Institute of Infectious Diseases, Tokyo, Japan,4 Department of Biomedical Chemistry, Graduate School of Medicine, University of Tokyo, Tokyo, Japan,5 The Asian Centre of International Parasite Control, Faculty of Tropical Medicine, Mahidol University, Thailand,6 Department of Medicine, Malaria Research Laboratory, Karolinska Institutet, Stockholm, Sweden7

Received 22 September 2006/ Returned for modification 1 December 2006/ Accepted 18 December 2006

Pyrimethamine resistance in Plasmodium falciparum has previously been shown to have emerged once in Southeast Asia, from where it spread to Africa. Pyrimethamine resistance in this parasite is known to be conferred by mutations in the gene encoding dihydrofolate reductase (dhfr). We have analyzed polymorphisms in dhfr as well as microsatellite haplotypes flanking this gene in a total of 285 isolates from different regions of Melanesia (Papua New Guinea, Vanuatu, and the Solomon Islands) and Southeast Asia (Thailand and Cambodia). Nearly all isolates (92%) in Melanesia were shown to carry a dhfr double mutation (CNRNI [underlining indicates the mutation]) at positions 50, 51, 59, 108, and 164, whereas 98% of Southeast Asian isolates were either triple (CIRNI) or quadruple (CIRNL) mutants. Microsatellite analysis revealed two distinct lineages of dhfr double mutants in Melanesia. One lineage had the same microsatellite haplotype as that previously reported for Southeast Asia and Africa, suggesting the spread of this allele to Melanesia from Southeast Asia. The other lineage had a unique, previously undescribed microsatellite haplotype, indicative of the de novo emergence of pyrimethamine resistance in Melanesia.

* Corresponding author. Mailing address: Department of International Affairs and Tropical Medicine, Tokyo Women's Medical University School of Medicine, 9-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. Phone: 81 3 5269 7422. Fax: 81 3 5269 7422. E-mail: hiro-tm{at}research.twmu.ac.jp.

{triangledown} Published ahead of print on 8 January 2007.

Antimicrobial Agents and Chemotherapy, March 2007, p. 1071-1077, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.01186-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Mita, T., Tanabe, K., Takahashi, N., Culleton, R., Ndounga, M., Dzodzomenyo, M., Akhwale, W. S., Kaneko, A., Kobayakawa, T. (2009). Indigenous evolution of Plasmodium falciparum pyrimethamine resistance multiple times in Africa. J Antimicrob Chemother 63: 252-255 [Abstract] [Full Text]  
  • Saito-Nakano, Y., Tanabe, K., Kamei, K., Iwagami, M., Komaki-Yasuda, K., Kawazu, S.-i., Kano, S., Ohmae, H., Endo, T. (2008). Genetic Evidence for Plasmodium falciparum Resistance to Chloroquine and Pyrimethamine in Indochina and the Western Pacific between 1984 and 1998. Am J Trop Med Hyg 79: 613-619 [Abstract] [Full Text]  


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