Genetic analysis of the dihydrofolate reductase-thymidylate synthase gene from geographically diverse isolates of Plasmodium malariae.
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]).
Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Naowarat
N
Tanomsing
Mallika
M
Imwong
Sasithon
S
Pukrittayakamee
Kesinee
K
Chotivanich
Sornchai
S
Looareesuwan
Mayfong
M
Mayxay
Christiane
C
Dolecek
Tran Tinh
TT
Hien
Virgilio E
VE
do Rosario
Ana Paula
AP
Arez
Pascal
P
Michon
Georges
G
Snounou
Nicholas J
NJ
White
Nicholas P J
NP
Day
D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D001208:Asia; D003001:Cloning, Molecular; D017931:DNA Primers; D016054:DNA, Protozoan / Q000235:genetics; D006801:Humans; D008288:Malaria / Q000469:parasitology / Q000523:psychology; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D021261:Parasitic Sensitivity Tests; D010802:Phylogeny; D010965:Plasmodium malariae / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*; D013940:Thymidylate Synthase / Q000235:genetics*
D000962:Antimalarials; D017931:DNA Primers; D016054:DNA, Protozoan; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase