Skip to main content
NCBI home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1995 Jan;39(1):61–65. doi: 10.1128/aac.39.1.61

Antimalarial action of hydroxamate-based iron chelators and potentiation of desferrioxamine action by reversed siderophores.

J Golenser 1, A Tsafack 1, Y Amichai 1, J Libman 1, A Shanzer 1, Z I Cabantchik 1
PMCID: PMC162485  PMID: 7695330

Abstract

Hydroxamate-based chelators of iron are potent inhibitors of in vitro growth of Plasmodium falciparum. Two types of such chelators, the natural desferrioxamine and the synthetic reversed siderophore RSFileum2, are prototypes of antimalarial agents whose action spectra differ in the speed of action, stage dependence, and degree of reversibility of effects. This work explores the possibility of improving the antimalarial efficacy of these agents by using them in various combinations on in vitro cultures of P. falciparum. Growth assessment was based both on total nucleic acid synthesis and on parasitemia. The results indicate that the synthetic reversed siderophore more than complements the antimalarial action of desferrioxamine when applied during either ring, trophozoite, or mixed stages. The combined drug effects were significantly higher than the additive effect of the individual drugs. Qualitatively similar results were obtained for both reversible effects and irreversible (i.e., sustained) effects. Following an 8-h window of exposure the combined drug treatment caused parasite growth arrest and prevented its recovery, even 3 days after the treatment. The fact that such a combination of iron chelators displays a wider action spectrum than either drug alone has implications for the design of chemotherapy regimens.

Full Text

The Full Text of this article is available as a PDF (203.8 KB).

Selected References

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

  1. Atkinson C. T., Bayne M. T., Gordeuk V. R., Brittenham G. M., Aikawa M. Stage-specific ultrastructural effects of desferrioxamine on Plasmodium falciparum in vitro. Am J Trop Med Hyg. 1991 Nov;45(5):593–601. doi: 10.4269/ajtmh.1991.45.593. [DOI] [PubMed] [Google Scholar]
  2. Basco L. K., Le Bras J. In vitro activity of chloroquine and quinine in combination with desferrioxamine against Plasmodium falciparum. Am J Hematol. 1993 Apr;42(4):389–391. doi: 10.1002/ajh.2830420411. [DOI] [PubMed] [Google Scholar]
  3. Berenbaum M. C. Criteria for analyzing interactions between biologically active agents. Adv Cancer Res. 1981;35:269–335. doi: 10.1016/s0065-230x(08)60912-4. [DOI] [PubMed] [Google Scholar]
  4. Cabantchik Z. L. Altered membrane transport of malaria-infected erythrocytes: a possible pharmacologic target. Blood. 1989 Oct;74(5):1464–1471. [PubMed] [Google Scholar]
  5. Fritsch G., Treumer J., Spira D. T., Jung A. Plasmodium vinckei: suppression of mouse infections with desferrioxamine B. Exp Parasitol. 1985 Oct;60(2):171–174. doi: 10.1016/0014-4894(85)90020-7. [DOI] [PubMed] [Google Scholar]
  6. Heppner D. G., Hallaway P. E., Kontoghiorghes G. J., Eaton J. W. Antimalarial properties of orally active iron chelators. Blood. 1988 Jul;72(1):358–361. [PubMed] [Google Scholar]
  7. Hershko C., Peto T. E. Deferoxamine inhibition of malaria is independent of host iron status. J Exp Med. 1988 Jul 1;168(1):375–387. doi: 10.1084/jem.168.1.375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Lambros C., Vanderberg J. P. Synchronization of Plasmodium falciparum erythrocytic stages in culture. J Parasitol. 1979 Jun;65(3):418–420. [PubMed] [Google Scholar]
  9. Loyevsky M., Lytton S. D., Mester B., Libman J., Shanzer A., Cabantchik Z. I. The antimalarial action of desferal involves a direct access route to erythrocytic (Plasmodium falciparum) parasites. J Clin Invest. 1993 Jan;91(1):218–224. doi: 10.1172/JCI116174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Lytton S. D., Mester B., Dayan I., Glickstein H., Libman J., Shanzer A., Cabantchik Z. I. Mode of action of iron (III) chelators as antimalarials: I. Membrane permeation properties and cytotoxic activity. Blood. 1993 Jan 1;81(1):214–221. [PubMed] [Google Scholar]
  11. Lytton S. D., Mester B., Libman J., Shanzer A., Cabantchik Z. I. Mode of action of iron (III) chelators as antimalarials: II. Evidence for differential effects on parasite iron-dependent nucleic acid synthesis. Blood. 1994 Aug 1;84(3):910–915. [PubMed] [Google Scholar]
  12. Moellering R. C., Jr Antimicrobial synergism--an elusive concept. J Infect Dis. 1979 Oct;140(4):639–641. doi: 10.1093/infdis/140.4.639. [DOI] [PubMed] [Google Scholar]
  13. Pollack S., Rossan R. N., Davidson D. E., Escajadillo A. Desferrioxamine suppresses Plasmodium falciparum in Aotus monkeys. Proc Soc Exp Biol Med. 1987 Feb;184(2):162–164. doi: 10.3181/00379727-184-42461. [DOI] [PubMed] [Google Scholar]
  14. Raventos-Suarez C., Pollack S., Nagel R. L. Plasmodium falciparum: inhibition of in vitro growth by desferrioxamine. Am J Trop Med Hyg. 1982 Sep;31(5):919–922. doi: 10.4269/ajtmh.1982.31.919. [DOI] [PubMed] [Google Scholar]
  15. Scheibel L. W., Adler A. Antimalarial activity of selected aromatic chelators. Mol Pharmacol. 1980 Sep;18(2):320–325. [PubMed] [Google Scholar]
  16. Scheibel L. W., Rodriguez S. Antimalarial activity of selected aromatic chelators V. Localization of 59Fe in Plasmodium falciparum in the presence of oxines. Prog Clin Biol Res. 1989;313:119–149. [PubMed] [Google Scholar]
  17. Scott M. D., Ranz A., Kuypers F. A., Lubin B. H., Meshnick S. R. Parasite uptake of desferroxamine: a prerequisite for antimalarial activity. Br J Haematol. 1990 Aug;75(4):598–602. doi: 10.1111/j.1365-2141.1990.tb07805.x. [DOI] [PubMed] [Google Scholar]
  18. Shanzer A., Libman J., Lytton S. D., Glickstein H., Cabantchik Z. I. Reversed siderophores act as antimalarial agents. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6585–6589. doi: 10.1073/pnas.88.15.6585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Stahel E., Mazier D., Guillouzo A., Miltgen F., Landau I., Mellouk S., Beaudoin R. L., Langlois P., Gentilini M. Iron chelators: in vitro inhibitory effect on the liver stage of rodent and human malaria. Am J Trop Med Hyg. 1988 Sep;39(3):236–240. doi: 10.4269/ajtmh.1988.39.236. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Whitehead S., Peto T. E. Stage-dependent effect of deferoxamine on growth of Plasmodium falciparum in vitro. Blood. 1990 Sep 15;76(6):1250–1255. [PubMed] [Google Scholar]
  22. van Zyl R. L., Havlik I., Monteagudo F. S. The combined effect of iron chelators and classical antimalarials on the in-vitro growth of Plasmodium falciparum. J Antimicrob Chemother. 1992 Sep;30(3):273–278. doi: 10.1093/jac/30.3.273. [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES