Pyrimethamine resistant mutations in Plasmodium falciparum

Mol Biochem Parasitol. 1992 Jun;52(2):149-57. doi: 10.1016/0166-6851(92)90047-n.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*


  • Multienzyme Complexes
  • Oligodeoxyribonucleotides
  • thymidylate synthase-dihydrofolate reductase
  • Tetrahydrofolate Dehydrogenase
  • Thymidylate Synthase
  • Pyrimethamine