Skip to main content
NCBI home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1994 May;38(5):997–1003. doi: 10.1128/aac.38.5.997

Iron chelators as therapeutic agents against Pneumocystis carinii.

G A Weinberg 1
PMCID: PMC188140  PMID: 8067783

Abstract

Iron plays a critical role in host-parasite interactions, and iron chelators have been demonstrated to serve as effective adjunct therapeutic agents against malaria. The effects of the parenteral iron chelator deferoxamine (DFO) on the growth of rat-derived Pneumocystis carinii were studied in a human fibroblast cell culture model and in two in vivo models of experimental infection. In addition, the effects of the investigational oral iron chelator CP20 and its 3-hydroxypyridin-4-one analogs CP51, CP94, and CP96 on the growth of P. carinii in vitro were assessed. DFO suppressed the growth of P. carinii in vitro in a dose-dependent manner, and daily injections of DFO markedly reduced the intensity of P. carinii infection in both mice and rats. Cell cultures treated with iron chelators that are administered orally to humans also showed substantial P. carinii growth inhibition. Reduction of P. carinii numbers after iron chelator therapy correlated with alterations in P. carinii morphology, as viewed by transmission electron microscopy. Since the use of current anti-P. carinii drugs is limited by toxicity or incomplete efficacy, or both, the role of iron chelation as adjunctive anti-P. carinii chemotherapy merits additional investigation.

Full text

PDF
997

Images in this article

1001Image
on p.1001

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. Bartlett M. S., Eichholtz R., Smith J. W. Antimicrobial susceptibility of Pneumocystis carinii in culture. Diagn Microbiol Infect Dis. 1985 Sep;3(5):381–387. doi: 10.1016/0732-8893(85)90076-8. [DOI] [PubMed] [Google Scholar]
  3. Bartlett M. S., Queener S. F., Durkin M. M., Shaw M. A., Smith J. W. Inoculated mouse model of Pneumocystis carinii infection. Diagn Microbiol Infect Dis. 1992 Feb;15(2):129–134. doi: 10.1016/0732-8893(92)90036-s. [DOI] [PubMed] [Google Scholar]
  4. Bartlett M. S., Queener S. F., Tidwell R. R., Milhous W. K., Berman J. D., Ellis W. Y., Smith J. W. 8-Aminoquinolines from Walter Reed Army Institute for Research for treatment and prophylaxis of Pneumocystis pneumonia in rat models. Antimicrob Agents Chemother. 1991 Feb;35(2):277–282. doi: 10.1128/aac.35.2.277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bartlett M. S., Smith J. W. Pneumocystis carinii, an opportunist in immunocompromised patients. Clin Microbiol Rev. 1991 Apr;4(2):137–149. doi: 10.1128/cmr.4.2.137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Berdoukas V., Bentley P., Frost H., Schnebli H. P. Toxicity of oral iron chelator L1. Lancet. 1993 Apr 24;341(8852):1088–1088. doi: 10.1016/0140-6736(93)92443-w. [DOI] [PubMed] [Google Scholar]
  7. Boelaert J. R., de Locht M., Van Cutsem J., Kerrels V., Cantinieaux B., Verdonck A., Van Landuyt H. W., Schneider Y. J. Mucormycosis during deferoxamine therapy is a siderophore-mediated infection. In vitro and in vivo animal studies. J Clin Invest. 1993 May;91(5):1979–1986. doi: 10.1172/JCI116419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Brittenham G. M. Development of iron-chelating agents for clinical use. Blood. 1992 Aug 1;80(3):569–574. [PubMed] [Google Scholar]
  9. Clarkson A. B., Jr, Sarić M., Grady R. W. Deferoxamine and eflornithine (DL-alpha-difluoromethylornithine) in a rat model of Pneumocystis carinii pneumonia. Antimicrob Agents Chemother. 1990 Sep;34(9):1833–1835. doi: 10.1128/aac.34.9.1833. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dobbin P. S., Hider R. C., Hall A. D., Taylor P. D., Sarpong P., Porter J. B., Xiao G., van der Helm D. Synthesis, physicochemical properties, and biological evaluation of N-substituted 2-alkyl-3-hydroxy-4(1H)-pyridinones: orally active iron chelators with clinical potential. J Med Chem. 1993 Aug 20;36(17):2448–2458. doi: 10.1021/jm00069a002. [DOI] [PubMed] [Google Scholar]
  11. Finkelstein R. A., Sciortino C. V., McIntosh M. A. Role of iron in microbe-host interactions. Rev Infect Dis. 1983 Sep-Oct;5 (Suppl 4):S759–S777. doi: 10.1093/clinids/5.supplement_4.s759. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. Goheen M. P., Blumershine R., Bartlett M. S., Hull M. T., Smith J. W. Improved intracellular morphology of Pneumocystis carinii from rat lung by postfixation with a mixture of potassium ferrocyanide and osmium tetroxide. Biotech Histochem. 1992 May;67(3):140–148. doi: 10.3109/10520299209110024. [DOI] [PubMed] [Google Scholar]
  14. Gordeuk V., Thuma P., Brittenham G., McLaren C., Parry D., Backenstose A., Biemba G., Msiska R., Holmes L., McKinley E. Effect of iron chelation therapy on recovery from deep coma in children with cerebral malaria. N Engl J Med. 1992 Nov 19;327(21):1473–1477. doi: 10.1056/NEJM199211193272101. [DOI] [PubMed] [Google Scholar]
  15. Hershko C. Development of oral iron chelator L1. Lancet. 1993 Apr 24;341(8852):1088–1089. doi: 10.1016/0140-6736(93)92444-x. [DOI] [PubMed] [Google Scholar]
  16. Hershko C., Gordeuk V. R., Thuma P. E., Theanacho E. N., Spira D. T., Hider R. C., Peto T. E., Brittenham G. M. The antimalarial effect of iron chelators: studies in animal models and in humans with mild falciparum malaria. J Inorg Biochem. 1992 Aug 15;47(3-4):267–277. doi: 10.1016/0162-0134(92)84072-u. [DOI] [PubMed] [Google Scholar]
  17. Hershko C. Iron chelators in medicine. Mol Aspects Med. 1992;13(2):113–165. doi: 10.1016/0098-2997(92)90013-p. [DOI] [PubMed] [Google Scholar]
  18. Hider R. C., Hall A. D. Clinically useful chelators of tripositive elements. Prog Med Chem. 1991;28:41–173. doi: 10.1016/s0079-6468(08)70363-1. [DOI] [PubMed] [Google Scholar]
  19. Kontoghiorghes G. J., Agarwal M. B., Tondury P., Kersten M. J., Jaeger M., Vreugdenhil G., Vania A., Rahman Y. E. Future of oral iron chelator deferiprone. (L1) ICOC committee. Lancet. 1993 Jun 5;341(8858):1479–1480. doi: 10.1016/0140-6736(93)90925-7. [DOI] [PubMed] [Google Scholar]
  20. Kontoghiorghes G. J., Aldouri M. A., Sheppard L., Hoffbrand A. V. 1,2-Dimethyl-3-hydroxypyrid-4-one, an orally active chelator for treatment of iron overload. Lancet. 1987 Jun 6;1(8545):1294–1295. doi: 10.1016/s0140-6736(87)90545-9. [DOI] [PubMed] [Google Scholar]
  21. Kontoghiorghes G. J., Barr J., Nortey P., Sheppard L. Selection of a new generation of orally active alpha-ketohydroxypyridine iron chelators intended for use in the treatment of iron overload. Am J Hematol. 1993 Apr;42(4):340–349. doi: 10.1002/ajh.2830420403. [DOI] [PubMed] [Google Scholar]
  22. Lee C. H., Bauer N. L., Shaw M. M., Durkin M. M., Bartlett M. S., Queener S. F., Smith J. W. Proliferation of rat Pneumocystis carinii on cells sheeted on microcarrier beads in spinner flasks. J Clin Microbiol. 1993 Jun;31(6):1659–1662. doi: 10.1128/jcm.31.6.1659-1662.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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]
  24. 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]
  25. Masur H. Prevention and treatment of pneumocystis pneumonia. N Engl J Med. 1992 Dec 24;327(26):1853–1860. doi: 10.1056/NEJM199212243272606. [DOI] [PubMed] [Google Scholar]
  26. Oppenheimer S. J. Iron and infection: the clinical evidence. Acta Paediatr Scand Suppl. 1989;361:53–62. doi: 10.1111/apa.1989.78.s361.53. [DOI] [PubMed] [Google Scholar]
  27. Payne S. M. Iron and virulence in the family Enterobacteriaceae. Crit Rev Microbiol. 1988;16(2):81–111. doi: 10.3109/10408418809104468. [DOI] [PubMed] [Google Scholar]
  28. Pfannkuch F., Bentley P., Schnebli H. P. Future of oral iron chelator deferiprone (L1) Lancet. 1993 Jun 5;341(8858):1480–1480. [PubMed] [Google Scholar]
  29. Porter J. B., Hider R. C., Huehns E. R. Update on the hydroxypyridinone oral iron-chelating agents. Semin Hematol. 1990 Apr;27(2):95–100. [PubMed] [Google Scholar]
  30. Porter J. B., Huehns E. R., Hider R. C. The development of iron chelating drugs. Baillieres Clin Haematol. 1989 Apr;2(2):257–292. doi: 10.1016/s0950-3536(89)80018-6. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. Robins-Browne R. M., Prpic J. K. Effects of iron and desferrioxamine on infections with Yersinia enterocolitica. Infect Immun. 1985 Mar;47(3):774–779. doi: 10.1128/iai.47.3.774-779.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. 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]
  34. 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]
  35. Sloand E., Laughon B., Armstrong M., Bartlett M. S., Blumenfeld W., Cushion M., Kalica A., Kovacs J. A., Martin W., Pitt E. The challenge of Pneumocystis carinii culture. J Eukaryot Microbiol. 1993 Mar-Apr;40(2):188–195. doi: 10.1111/j.1550-7408.1993.tb04902.x. [DOI] [PubMed] [Google Scholar]
  36. Summers M. R., Jacobs A., Tudway D., Perera P., Ricketts C. Studies in desferrioxamine and ferrioxamine metabolism in normal and iron-loaded subjects. Br J Haematol. 1979 Aug;42(4):547–555. doi: 10.1111/j.1365-2141.1979.tb01167.x. [DOI] [PubMed] [Google Scholar]
  37. Traore O., Carnevale P., Kaptue-Noche L., M'Bede J., Desfontaine M., Elion J., Labie D., Nagel R. L. Preliminary report on the use of desferrioxamine in the treatment of Plasmodium falciparum malaria. Am J Hematol. 1991 Jul;37(3):206–208. doi: 10.1002/ajh.2830370316. [DOI] [PubMed] [Google Scholar]
  38. Weinberg E. D. Cellular iron metabolism in health and disease. Drug Metab Rev. 1990;22(5):531–579. doi: 10.3109/03602539008991450. [DOI] [PubMed] [Google Scholar]
  39. Weinberg E. D. Cellular regulation of iron assimilation. Q Rev Biol. 1989 Sep;64(3):261–290. doi: 10.1086/416359. [DOI] [PubMed] [Google Scholar]
  40. Weinberg E. D. Iron and infection. Microbiol Rev. 1978 Mar;42(1):45–66. doi: 10.1128/mr.42.1.45-66.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Weinberg E. D. Iron withholding: a defense against infection and neoplasia. Physiol Rev. 1984 Jan;64(1):65–102. doi: 10.1152/physrev.1984.64.1.65. [DOI] [PubMed] [Google Scholar]
  42. Weinberg G. A., Shaw M. M. Suppressive effect of deferoxamine on the growth of Pneumocystis carinii in vitro. J Protozool. 1991 Nov-Dec;38(6):223S–224S. [PubMed] [Google Scholar]
  43. 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]
  44. Yinnon A. M., Theanacho E. N., Grady R. W., Spira D. T., Hershko C. Antimalarial effect of HBED and other phenolic and catecholic iron chelators. Blood. 1989 Nov 1;74(6):2166–2171. [PubMed] [Google Scholar]

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

RESOURCES