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Antimicrobial Agents and Chemotherapy, October 2007, p. 3523-3530, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.00234-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Genetic Analysis of the Dihydrofolate Reductase-Thymidylate Synthase Gene from Geographically Diverse Isolates of Plasmodium malariae

Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand,¹ Wellcome Trust-Mahosot Hospital-Oxford Tropical Medicine Research Collaboration, Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao PDR,² Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam,³ Centro de Malária e outras Doenças Tropicais, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Rua da Junqueira 96, 1349-008 Lisboa, Portugal,⁴ Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea,⁵ Parasitologie Comparée et Modèles Expérimentaux USM0307, CNRS IFR101, Muséum National d'Histoire Naturelle, CP52, 61 Rue Buffon, 75231 Paris Cedex 05, France,⁶ Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom⁷

Received 16 February 2007/ Returned for modification 1 May 2007/ Accepted 28 July 2007

Plasmodium malariae, the parasite responsible for quartan malaria, is transmitted in most areas of malaria endemicity and is associated with significant morbidity. The sequence of the gene coding for the enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS) was obtained from field isolates of P. malariae and from the closely related simian parasite Plasmodium brasilianum. The two sequences were nearly 100% homologous, adding weight to the notion that they represent genetically distinct lines of the same species. A survey of polymorphisms of the dhfr sequences in 35 isolates of P. malariae collected from five countries in Asia and Africa revealed a low number of nonsynonymous mutations in five codons. In five of the isolates collected from southeast Asia, a nonsynonymous mutation was found at one of the three positions known to be associated with antifolate resistance in other Plasmodium species. Five isolates with the wild-type DHFR could be assayed for drug susceptibility in vitro and were found to be sensitive to pyrimethamine (mean 50% inhibitory concentration, 2.24 ng/ml [95% confidence interval, 0.4 to 3.1]).

Published ahead of print on 6 August 2007.