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DIHYDROFOLATE REDUCTASE AND DIHYDROPTEROATE SYNTHASE GENOTYPES ASSOCIATED WITH IN VITRO RESISTANCE OF PLASMODIUM FALCIPARUM TO PYRIMETHAMINE, TRIMETHOPRIM, SULFADOXINE, AND SULFAMETHOXAZOLE

A total of 70 Plasmodium falciparum isolates were tested in vitro against pyrimethamine (PYR), tri-methoprim (TRM), sulfadoxine (SDX), and sulfamethoxazole (SMX), and their dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genotypes were determined. dhfr genotypes correlated with PYR and TRM drug responses (r = 0.93 and 0.85). Isolates with wild-type alleles showed mean half inhibitory concentrations (IC₅₀ ± SD) of 0.10 ± 0.10 and 0.15 ± 0.06 µg/100 µl for PYR and TRM. Parasites with mutations at codons 108 and 51 alone or combined with codon 59 have IC₅₀ of 11.46 ± 0.86 (PYR) and 2.90 ± 0.59 µg/100 µl (TRM). For both drugs, the differences in the mean IC₅₀ between wild and mutant parasites were statistically significant (P < 0.001). Isolates with mixed wild and mutant alleles showed an intermediate level of susceptibility. Our data show partial cross-resistance between PYR/TRM and SDX/SMX (r = 0.85 and 0.65). Correlation was not observed between different dhps genotypes and the in vitro outcome to SDX and SMX (r = 0.30 and 0.34). The lack of correlation could be due to folates and para-aminobenzoic acid in the RPMI medium and the serum used to supplement the cultures.

Acknowledgments: We thank Mr. Jimmy Weng, for technical assistance; Dr. Thor Theander and Dr. Donath Tarimo, for critical comments and help; and the Malaria Research Group in the Biochemistry Department, Faculty of Medicine, University of Khartoum.

Financial support: This work was supported by the Danish International Development Agency (DANIDA).

Authors’ Addresses: Insaf Khalil and Michael Alifrangis, Center for Medical Parasitology, Institute of Medical Microbiology and Immunology, University of Copenhagen, Panum Institute, Building 24.2, Blegdamsvej 3, 2200 Copenhagen N, Denmark and Department of Infectious Diseases, Copenhagen University Hospital, Tagensvej 20, 2200 Copenhagen N, Denmark. Anita M. Rønn, Department of Clinical Pharmacology, Copenhagen University Hospital, Tagensvej 20, 2200, Copenhagen N, Denmark. Haytham A. Gabar, Department of Biochemistry, Faculty of Medicine, University of Khartoum, Sudan, P.O. Box 102. Gwiria M. H. Satti, Department of Biochemistry, P.O. Box 2114, King Faisal University, Dammam, Saudi Arabia. Ib C. Bygbjerg, Institute of Public Health, University of Copenhagen, Panum Institute, Building 42, Blegdamsvej 3, 2200 Copenhagen N, Denmark.

Reprint requests: Insaf Khalil, Center for Medical Parasitology, Institute of Medical Microbiology and Immunology, University of Copenhagen, Panum Institute, Building 24,2, Blegdamsvej 3, 2200, Copenhagen N, Denmark, Telephone: + 45 35 32 76 80, Fax: + 45 35 32 78 51, E-mail: InsafK{at}hotmail.com

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