Mechanism of pyrimethamine resistance in recent isolates of plasmodium falciparum

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dc.contributor.authorMcCutchan, T.F.
dc.contributor.authorWelsh, J.A.
dc.contributor.authorDame, J.B.
dc.contributor.authorQuakyi, I.A.
dc.contributor.authorGraves, P.M.
dc.contributor.authorDrake, J.C.
dc.contributor.authorAllegra, C.J.
dc.date.accessioned2013-06-21T12:28:53Z
dc.date.accessioned2017-10-16T12:29:24Z
dc.date.available2013-06-21T12:28:53Z
dc.date.available2017-10-16T12:29:24Z
dc.date.issued1984
dc.description.abstractClones of Plasmodium falciparum prepared from recent isolates of infected blood were studied to determine the molecular mechanism of naturally occurring pyrimethamine resistance. Total DNA, as well as thymidylate synthetase and dihydrofolate reductase activities, were characterized from these lines. Restriction analysis of DNA from pyrimethamine-susceptible and -resistant lines of the parasite showed no obvious amplification of any DNA fragment. Further, analysis of DNA from resistant and susceptible lines by centrifugation in cesium chloride-ethidium bromide revealed no extrachromosomal amplification in the resistant line. Comparison of the dihydrofolate reductase enzyme activity in the two lines revealed similar K(m)s for substrate but a large difference in the inhibition constant for pyrimethamine. Additionally, the enzyme from the resistant line was considerably more stable in vitro than the corresponding enzyme from the susceptible line. The thymidylate synthetase activity in the two lines was similar and unaffected by pyrimethamine. The mechanism of drug resistance in this isolate involves altered properties of the dihydrofolate reductase conferring both a different affinity for the drug and increased stability.en_US
dc.identifier.citationMcCutchan, T. F., Welsh, J. A., Dame, J. B., Quakyi, I. A., Graves, P. M., Drake, J. C., & Allegra, C. J. (1984). Mechanism of pyrimethamine resistance in recent isolates of plasmodium falciparum. Antimicrobial Agents and Chemotherapy, 26(5), 656-659en_US
dc.identifier.issn00664804
dc.identifier.urihttp://197.255.68.203/handle/123456789/3803
dc.language.isoenen_US
dc.publisherAntimicrobial Agents and Chemotherapyen_US
dc.subjectEMTREE drug terms: dihydrofolate reductase; pyrimethamineen_US
dc.subjectEMTREE medical terms: animal cell; drug mechanism; drug resistance; malaria; nonhuman; plasmodium falciparum; priority journal; protozoonen_US
dc.subjectMeSH: Animals; Clone Cells; DNA; Drug Resistance, Microbial; Kinetics; Methotrexate; Plasmodium falciparum; Pyrimethamine; Tetrahydrofolate Dehydrogenase; Thymidylate Synthaseen_US
dc.titleMechanism of pyrimethamine resistance in recent isolates of plasmodium falciparumen_US
dc.typeArticleen_US

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