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. 1996 Mar;40(3):602–608. doi: 10.1128/aac.40.3.602

Differential in vitro activities of ionophore compounds against Plasmodium falciparum and mammalian cells.

C Gumila 1, M L Ancelin 1, G Jeminet 1, A M Delort 1, G Miquel 1, H J Vial 1
PMCID: PMC163165  PMID: 8851578

Abstract

Twenty-two ionophore compounds were screened for their antimalarial activities. They consisted of true ionophores (mobile carriers) and channel-forming quasi-ionophores with different ionic specificities. Eleven of the compounds were found to be extremely efficient inhibitors of Plasmodium falciparum growth in vitro, with 50% inhibitory concentrations of less than 10 ng/ml. Gramicidin D was the most active compound tested, with 50% inhibitory concentration of 0.035 ng/ml. Compounds with identical ionic specificities generally had similar levels of antimalarial activity, and ionophores specific to monovalent cations were the most active. Compounds were further tested to determine their in vitro toxicities against mammalian lymphoblast and macrophage cell lines. Nine of the 22 compounds, i.e., alborixin, lonomycin, nigericin, narasin, monensin and its methylated derivative, lasalocid and its bromo derivative, and gramicidin D, most specific to monovalent cations, were at least 35-fold more active in vitro against P. falciparum than against the two other mammalian cell lines. The enhanced ability to penetrate the erythrocyte membrane after infection could be a factor that determines ionophore selectivity for infected erythrocytes.

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Selected References

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  1. Adovelande J., Bastide B., Délèze J., Schrével J. Cytosolic free calcium in Plasmodium falciparum-infected erythrocytes and the effect of verapamil: a cytofluorimetric study. Exp Parasitol. 1993 May;76(3):247–258. doi: 10.1006/expr.1993.1030. [DOI] [PubMed] [Google Scholar]
  2. Cabantchik Z. I. Properties of permeation pathways induced in the human red cell membrane by malaria parasites. Blood Cells. 1990;16(2-3):421–432. [PubMed] [Google Scholar]
  3. Chapel M., Jeminet G., Gachon P., Debise R., Durand R. Comparative effects of ionophores grisorixin, alborixin and two derivatives on K+ glutamate efflux in rat liver mitochondria. J Antibiot (Tokyo) 1979 Jul;32(7):740–745. doi: 10.7164/antibiotics.32.740. [DOI] [PubMed] [Google Scholar]
  4. Desjardins R. E., Canfield C. J., Haynes J. D., Chulay J. D. Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique. Antimicrob Agents Chemother. 1979 Dec;16(6):710–718. doi: 10.1128/aac.16.6.710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Divo A. A., Geary T. G., Jensen J. B. Oxygen- and time-dependent effects of antibiotics and selected mitochondrial inhibitors on Plasmodium falciparum in culture. Antimicrob Agents Chemother. 1985 Jan;27(1):21–27. doi: 10.1128/aac.27.1.21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Elford B. C., Cowan G. M., Ferguson D. J. Parasite-regulated membrane transport processes and metabolic control in malaria-infected erythrocytes. Biochem J. 1995 Jun 1;308(Pt 2):361–374. doi: 10.1042/bj3080361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Elliott J. R., Needham D., Dilger J. P., Haydon D. A. The effects of bilayer thickness and tension on gramicidin single-channel lifetime. Biochim Biophys Acta. 1983 Oct 26;735(1):95–103. doi: 10.1016/0005-2736(83)90264-x. [DOI] [PubMed] [Google Scholar]
  8. Eytan G. D., Broza R., Shalitin Y. Gramicidin S and dodecylamine induce leakage and fusion of membranes at micromolar concentrations. Biochim Biophys Acta. 1988 Jan 22;937(2):387–397. doi: 10.1016/0005-2736(88)90261-1. [DOI] [PubMed] [Google Scholar]
  9. Gero A. M., O'Sullivan W. J. Purines and pyrimidines in malarial parasites. Blood Cells. 1990;16(2-3):467–498. [PubMed] [Google Scholar]
  10. Ginsburg H., Handeli S., Friedman S., Gorodetsky R., Krugliak M. Effects of red blood cell potassium and hypertonicity on the growth of Plasmodium falciparum in culture. Z Parasitenkd. 1986;72(2):185–199. doi: 10.1007/BF00931146. [DOI] [PubMed] [Google Scholar]
  11. Ginsburg H. Transport pathways in the malaria-infected erythrocyte. Their characterization and their use as potential targets for chemotherapy. Biochem Pharmacol. 1994 Nov 16;48(10):1847–1856. doi: 10.1016/0006-2952(94)90582-7. [DOI] [PubMed] [Google Scholar]
  12. Goodrich R. D., Garrett J. E., Gast D. R., Kirick M. A., Larson D. A., Meiske J. C. Influence of monensin on the performance of cattle. J Anim Sci. 1984 Jun;58(6):1484–1498. doi: 10.2527/jas1984.5861484x. [DOI] [PubMed] [Google Scholar]
  13. Jensen J. B., Trager W. Plasmodium falciparum in culture: use of outdated erthrocytes and description of the candle jar method. J Parasitol. 1977 Oct;63(5):883–886. [PubMed] [Google Scholar]
  14. Killian J. A. Gramicidin and gramicidin-lipid interactions. Biochim Biophys Acta. 1992 Dec 11;1113(3-4):391–425. doi: 10.1016/0304-4157(92)90008-x. [DOI] [PubMed] [Google Scholar]
  15. Kovác L., Böhmerová E., Butko P. Ionophores and intact cells. I. Valinomycin and nigericin act preferentially on mitochondria and not on the plasma membrane of Saccharomyces cerevisiae. Biochim Biophys Acta. 1982 Dec 30;721(4):341–348. doi: 10.1016/0167-4889(82)90088-x. [DOI] [PubMed] [Google Scholar]
  16. Kramer R., Ginsburg H. Calcium transport and compartment analysis of free and exchangeable calcium in Plasmodium falciparum-infected red blood cells. J Protozool. 1991 Nov-Dec;38(6):594–601. [PubMed] [Google Scholar]
  17. Krogstad D. J., Sutera S. P., Marvel J. S., Gluzman I. Y., Boylan C. W., Colca J. R., Williamson J. R., Schlesinger P. H. Calcium and the malaria parasite: parasite maturation and the loss of red cell deformability. Blood Cells. 1991;17(1):229–248. [PubMed] [Google Scholar]
  18. Lee P., Ye Z., Van Dyke K., Kirk R. G. X-ray microanalysis of Plasmodium falciparum and infected red blood cells: effects of qinghaosu and chloroquine on potassium, sodium, and phosphorus composition. Am J Trop Med Hyg. 1988 Aug;39(2):157–165. doi: 10.4269/ajtmh.1988.39.157. [DOI] [PubMed] [Google Scholar]
  19. McColm A. A., McHardy N. Evaluation of a range of antimicrobial agents against the parasitic protozoa, Plasmodium falciparum, Babesia rodhaini and Theileria parva in vitro. Ann Trop Med Parasitol. 1984 Aug;78(4):345–354. doi: 10.1080/00034983.1984.11811831. [DOI] [PubMed] [Google Scholar]
  20. Mikkelsen R. B., Tanabe K., Wallach D. F. Membrane potential of Plasmodium-infected erythrocytes. J Cell Biol. 1982 Jun;93(3):685–689. doi: 10.1083/jcb.93.3.685. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Mikkelsen R. B., Wallach D. F., Van Doren E., Nillni E. A. Membrane potential of erythrocytic stages of Plasmodium chabaudi free of the host cell membrane. Mol Biochem Parasitol. 1986 Oct;21(1):83–92. doi: 10.1016/0166-6851(86)90082-4. [DOI] [PubMed] [Google Scholar]
  22. Moll G. N., Vial H. J., van der Wiele F. C., Ancelin M. L., Roelofsen B., Slotboom A. J., de Haas G. H., van Deenen L. L., Op den Kamp J. A. Selective elimination of malaria infected erythrocytes by a modified phospholipase A2 in vitro. Biochim Biophys Acta. 1990 May 9;1024(1):189–192. doi: 10.1016/0005-2736(90)90224-c. [DOI] [PubMed] [Google Scholar]
  23. Moll G. N., van den Eertwegh V., Tournois H., Roelofsen B., Op den Kamp J. A., van Deenen L. L. Growth inhibition of Plasmodium falciparum in in vitro cultures by selective action of tryptophan-N-formylated gramicidin incorporated in lipid vesicles. Biochim Biophys Acta. 1991 Feb 25;1062(2):206–210. doi: 10.1016/0005-2736(91)90394-n. [DOI] [PubMed] [Google Scholar]
  24. Ovchinnikov Y. A. Physico-chemical basis of ion transport through biological membranes: ionophores and ion channels. Eur J Biochem. 1979 Mar;94(2):321–336. doi: 10.1111/j.1432-1033.1979.tb12898.x. [DOI] [PubMed] [Google Scholar]
  25. Pressman B. C. Biological applications of ionophores. Annu Rev Biochem. 1976;45:501–530. doi: 10.1146/annurev.bi.45.070176.002441. [DOI] [PubMed] [Google Scholar]
  26. Raether W., Seidenath H., Mehlhorn H., Ganster H. J. The action of salinomycin-Na and lasalocid-Na on chloroquine- and mepacrine-resistant line of Plasmodium berghei K 173-strain in Wistar rats. Z Parasitenkd. 1985;71(5):567–574. doi: 10.1007/BF00925589. [DOI] [PubMed] [Google Scholar]
  27. Richards W. H., Maples B. K. Studies on Plasmodium falciparum in continuous cultivation. I. The effect of chloroquine and pyrimethamine on parasite growth and viability. Ann Trop Med Parasitol. 1979 Apr;73(2):99–108. [PubMed] [Google Scholar]
  28. Roth E., Jr Plasmodium falciparum carbohydrate metabolism: a connection between host cell and parasite. Blood Cells. 1990;16(2-3):453–466. [PubMed] [Google Scholar]
  29. Sansom M. S. Alamethicin and related peptaibols--model ion channels. Eur Biophys J. 1993;22(2):105–124. doi: 10.1007/BF00196915. [DOI] [PubMed] [Google Scholar]
  30. Tanabe K., Doi S. Rapid clearance of Plasmodium yoelii-infected erythrocytes after exposure to the ionophore A23187. Comp Biochem Physiol A Comp Physiol. 1989;92(1):85–89. doi: 10.1016/0300-9629(89)90746-9. [DOI] [PubMed] [Google Scholar]
  31. Tanabe K. Ion metabolism in malaria-infected erythrocytes. Blood Cells. 1990;16(2-3):437–449. [PubMed] [Google Scholar]
  32. Vial H. J., Ancelin M. L. Malarial lipids. An overview. Subcell Biochem. 1992;18:259–306. [PubMed] [Google Scholar]
  33. Vial H. J., Thuet M. J., Philippot J. R. Inhibition of the in vitro growth of Plasmodium falciparum by D vitamins and vitamin D-3 derivatives. Mol Biochem Parasitol. 1982 Mar;5(3):189–198. doi: 10.1016/0166-6851(82)90020-2. [DOI] [PubMed] [Google Scholar]
  34. Wasserman M., Alarcón C., Mendoza P. M. Effects of Ca++ depletion on the asexual cell cycle of Plasmodium falciparum. Am J Trop Med Hyg. 1982 Jul;31(4):711–717. doi: 10.4269/ajtmh.1982.31.711. [DOI] [PubMed] [Google Scholar]
  35. Westley J. W., Oliveto E. P., Berger J., Evans R. H., Jr, Glass R., Stempel A., Toome V., Williams T. Chemical transformations of antibiotic X-537A and their effect on antibacterial activity. J Med Chem. 1973 Apr;16(4):397–403. doi: 10.1021/jm00262a020. [DOI] [PubMed] [Google Scholar]
  36. Woolley G. A., Wallace B. A. Model ion channels: gramicidin and alamethicin. J Membr Biol. 1992 Aug;129(2):109–136. doi: 10.1007/BF00219508. [DOI] [PubMed] [Google Scholar]

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