Pyrimethamine resistant mutations in Plasmodium falciparum

Pyrimethamine resistant mutations in Plasmodium falciparum

Three mutations in Plasmodium falciparum yielding increased resistance to pyrimethamine were obtained following treatment with chemical mutagens and selection in presence of pyrimethamine. From parasite clone TM4/8.2 a mutant, TM4/8.2/4.1, was produced which raised pyrimethamine resistance about 500...

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Bibliographic Details
Published in:Molecular and biochemical parasitology Vol. 52; no. 2; p. 149
Main Authors: Thaithong, S, Chan, S W, Songsomboon, S, Wilairat, P, Seesod, N, Sueblinwong, T, Goman, M, Ridley, R, Beale, G
Format: Journal Article
Language:English
Published: Netherlands 01-06-1992
Subjects:
Animals
Base Sequence
Drug Resistance - genetics
Humans
Malaria, Falciparum - parasitology
Molecular Sequence Data
Multienzyme Complexes - chemistry
Multienzyme Complexes - genetics
Mutagenesis
Mutation
Oligodeoxyribonucleotides - genetics
Plasmodium falciparum - drug effects
Plasmodium falciparum - enzymology
Plasmodium falciparum - genetics
Polymerase Chain Reaction
Pyrimethamine - pharmacology
Tetrahydrofolate Dehydrogenase - chemistry
Tetrahydrofolate Dehydrogenase - genetics
Thymidylate Synthase - chemistry
Thymidylate Synthase - genetics
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Summary:Three mutations in Plasmodium falciparum yielding increased resistance to pyrimethamine were obtained following treatment with chemical mutagens and selection in presence of pyrimethamine. From parasite clone TM4/8.2 a mutant, TM4/8.2/4.1, was produced which raised pyrimethamine resistance about 500 times and was found to involve an amino acid change in the DHFR-TS enzyme molecule from Ser108 to Asn108. A clone of another isolate, T9/94, yielded a mutant, T9/94/300.300, raising pyrimethamine resistance about 10 times and involving an amino acid change from Ile164 to Met164. However, another mutant from T9/94, T9/94/M1-1(b3), although it raised the pyrimethamine resistance 100 times, did not involve any changes in the coding sequence of the DHFR-TS gene, but resulted in the production of about twice as much DHFR-TS enzyme as the original clone T9/94. No amplification of the DHFR-TS gene was detected. It is concluded that changes in pyrimethamine resistance of malaria parasites may arise in at least 2 ways: (1) by structural changes in the DHFR domain of the DHFR-TS gene (as previously found by other workers); (2) by other changes, possibly affecting the expression of the DHFR-TS gene. The relative importance of these 2 mechanisms in causing resistance in wild populations of P. falciparum is discussed.
ISSN:0166-6851
DOI:10.1016/0166-6851(92)90047-N