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. 1991 Feb;35(2):267–271. doi: 10.1128/aac.35.2.267

Inhibition of Plasmodium falciparum dihydropteroate synthetase and growth in vitro by sulfa drugs.

Y Zhang 1, S R Meshnick 1
PMCID: PMC244989  PMID: 2024960

Abstract

The Michaelis-Menten inhibitory constants (Kis) and the concentrations required for 50% inhibition of the Plasmodium falciparum dihydropteroate synthetase were determined for six sulfa drugs. These drugs inhibited the in vitro growth of P. falciparum (50% lethal concentration) at concentrations of 30 to 500 nM; these concentrations were 100 to 1,000 times lower than the concentrations required for 50% inhibition and Kis (6 to 500 microM). The uptake of p-aminobenzoic acid was not inhibited by the sulfa drugs. However, infected erythrocytes took up more labeled sulfamethoxazole than did uninfected erythrocytes. Thus, the concentration of sulfa drugs by malaria parasites may explain how sulfa drugs inhibit in vitro growth of parasites through the inhibition of dihydropteroate synthetase.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1006/abio.1976.9999. [DOI] [PubMed] [Google Scholar]
  2. Brockelman C. R., Tan-ariya P. Plasmodium falciparum in continuous culture: a new medium for the in vitro test for sulfadoxine sensitivity. Bull World Health Organ. 1982;60(3):423–426. [PMC free article] [PubMed] [Google Scholar]
  3. Chulay J. D., Watkins W. M., Sixsmith D. G. Synergistic antimalarial activity of pyrimethamine and sulfadoxine against Plasmodium falciparum in vitro. Am J Trop Med Hyg. 1984 May;33(3):325–330. doi: 10.4269/ajtmh.1984.33.325. [DOI] [PubMed] [Google Scholar]
  4. Dieckmann A., Jung A. Mechanisms of sulfadoxine resistance in Plasmodium falciparum. Mol Biochem Parasitol. 1986 May;19(2):143–147. doi: 10.1016/0166-6851(86)90119-2. [DOI] [PubMed] [Google Scholar]
  5. Fairfield A. S., Meshnick S. R., Eaton J. W. Malaria parasites adopt host cell superoxide dismutase. Science. 1983 Aug 19;221(4612):764–766. doi: 10.1126/science.6348944. [DOI] [PubMed] [Google Scholar]
  6. Ferone R. The enzymic synthesis of dihydropteroate and dihydrofolate by Plasmodium berghei. J Protozool. 1973 Aug;20(3):459–464. doi: 10.1111/j.1550-7408.1973.tb00926.x. [DOI] [PubMed] [Google Scholar]
  7. McCullough J. L., Maren T. H. Dihydropteroate synthetase from Plasmodium berghei: isolation, properties, and inhibition by dapsone and sulfadiazine. Mol Pharmacol. 1974 Jan;10(1):140–145. [PubMed] [Google Scholar]
  8. McCullough J. L., Maren T. H. Inhibition of dihydropteroate synthetase from Escherichia coli by sulfones and sulfonamides. Antimicrob Agents Chemother. 1973 Jun;3(6):665–669. doi: 10.1128/aac.3.6.665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Merali S., Zhang Y., Sloan D., Meshnick S. Inhibition of Pneumocystis carinii dihydropteroate synthetase by sulfa drugs. Antimicrob Agents Chemother. 1990 Jun;34(6):1075–1078. doi: 10.1128/aac.34.6.1075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. SHIOTA T., DISRAELY M. N., MCCANN M. P. THE ENZYMATIC SYNTHESIS OF FOLATE-LIKE COMPOUNDS FROM HYDROXYMETHYLDIHYDROPTERIDINE PYROPHOSPHATE. J Biol Chem. 1964 Jul;239:2259–2266. [PubMed] [Google Scholar]
  11. Scott H. V., Rieckmann K. H., O'Sullivan W. J. Synergistic antimalarial activity of dapsone/dihydrofolate reductase inhibitors and the interaction of antifol, antipyrimidine and antipurine combinations against Plasmodium falciparum in vitro. Trans R Soc Trop Med Hyg. 1987;81(5):715–721. doi: 10.1016/0035-9203(87)90004-6. [DOI] [PubMed] [Google Scholar]
  12. Sixsmith D. G., Watkins W. M., Chulay J. D., Spencer H. C. In vitro antimalarial activity of tetrahydrofolate dehydrogenase inhibitors. Am J Trop Med Hyg. 1984 Sep;33(5):772–776. doi: 10.4269/ajtmh.1984.33.772. [DOI] [PubMed] [Google Scholar]
  13. Stitt V. J., Jr Stevens-Johnson syndrome: a review of the literature. J Natl Med Assoc. 1988 Jan;80(1):104, 106-8. [PMC free article] [PubMed] [Google Scholar]
  14. Trager W., Jensen J. B. Human malaria parasites in continuous culture. Science. 1976 Aug 20;193(4254):673–675. doi: 10.1126/science.781840. [DOI] [PubMed] [Google Scholar]
  15. Walter R. D., Königk E. 7,8-Dihydropteroate-synthesizing enzyme from Plasmodium chabaudi. Methods Enzymol. 1980;66:564–570. doi: 10.1016/0076-6879(80)66508-2. [DOI] [PubMed] [Google Scholar]
  16. Warhurst D. C. Antimalarial drugs. An update. Drugs. 1987 Jan;33(1):50–65. doi: 10.2165/00003495-198733010-00003. [DOI] [PubMed] [Google Scholar]
  17. Watkins W. M., Sixsmith D. G., Chulay J. D., Spencer H. C. Antagonism of sulfadoxine and pyrimethamine antimalarial activity in vitro by p-aminobenzoic acid, p-aminobenzoylglutamic acid and folic acid. Mol Biochem Parasitol. 1985 Jan;14(1):55–61. doi: 10.1016/0166-6851(85)90105-7. [DOI] [PubMed] [Google Scholar]

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