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. 1995 Aug;39(8):1824–1829. doi: 10.1128/aac.39.8.1824

Inhibition of growth of Histoplasma capsulatum yeast cells in human macrophages by the iron chelator VUF 8514 and comparison of VUF 8514 with deferoxamine.

S L Newman 1, L Gootee 1, V Stroobant 1, H van der Goot 1, J R Boelaert 1
PMCID: PMC162833  PMID: 7486926

Abstract

Histoplasma capsulatum requires intracellular iron to survive and multiply within human and murine macrophages (M phi). Thus, iron chelators may be useful compounds in the treatment of histoplasmosis. In the present study we compared the efficacies of five different iron chelators with deferoxamine (DEF) for their capacity to inhibit the growth of H. capsulatum yeast cells in culture medium and within human M phi. Of the agents tested, only one, VUF 8514, a 2,2'-bipyridyl analog, was found to be effective. VUF 8514 inhibited the growth of yeast cells in tissue culture medium and within M phi in a dose-response fashion. In tissue culture medium, the 50% effective dose (ED50) of VUF 8514 was 30 nM and the ED50 of DEF was 1 mM. In human M phi, the ED50 of VUF 8514 was 520 nM and the ED50 of DEF was 4 mM. Thus, VUF 8514 was effective at a concentration 7.7 x 10(3)-fold lower than DEF in inhibiting the growth of yeast cells in M phi. Inhibition of the intracellular growth of yeast cells by VUF 8514 was reversed by holotransferrin and iron nitriloacetate, an iron compound that is soluble at neutral to alkaline pH. Thus, VUF 8514 inhibits the intracellular growth of yeast cells by acting as an iron chelator rather than through its capacity as a weak base. These data suggest that the hydroxamic acid siderophore of H. capsulatum yeast cells competes successfully for iron against some iron chelators but not others and that VUF 8514 may be a potential therapeutic agent for the treatment of histoplasmosis.

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Selected References

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  1. Bates G. W., Wernicke J. The kinetics and mechanism of iron(3) exchange between chelates and transferrin. IV. The reaction of transferrin with iron(3) nitrilotriacetate. J Biol Chem. 1971 Jun 10;246(11):3679–3685. [PubMed] [Google Scholar]
  2. Baynes R., Bukofzer G., Bothwell T., Bezwoda W., Macfarlane B. Transferrin receptors and transferrin iron uptake by cultured human blood monocytes. Eur J Cell Biol. 1987 Jun;43(3):372–376. [PubMed] [Google Scholar]
  3. Bergeron R. J., Wollenweber M., Wiegand J. An investigation of desferrithiocin metabolism. J Med Chem. 1994 Sep 2;37(18):2889–2895. doi: 10.1021/jm00044a009. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Bullock W. E., Wright S. D. Role of the adherence-promoting receptors, CR3, LFA-1, and p150,95, in binding of Histoplasma capsulatum by human macrophages. J Exp Med. 1987 Jan 1;165(1):195–210. doi: 10.1084/jem.165.1.195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Burt W. R. Identification of coprogen B and its breakdown products from Histoplasma capsulatum. Infect Immun. 1982 Mar;35(3):990–996. doi: 10.1128/iai.35.3.990-996.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Burt W. R., Underwood A. L., Appleton G. L. Hydroxamic acid from Histoplasma capsulatum that displays growth factor activity. Appl Environ Microbiol. 1981 Sep;42(3):560–563. doi: 10.1128/aem.42.3.560-563.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Byrd T. F., Horwitz M. A. Chloroquine inhibits the intracellular multiplication of Legionella pneumophila by limiting the availability of iron. A potential new mechanism for the therapeutic effect of chloroquine against intracellular pathogens. J Clin Invest. 1991 Jul;88(1):351–357. doi: 10.1172/JCI115301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dautry-Varsat A., Ciechanover A., Lodish H. F. pH and the recycling of transferrin during receptor-mediated endocytosis. Proc Natl Acad Sci U S A. 1983 Apr;80(8):2258–2262. doi: 10.1073/pnas.80.8.2258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dhople A. M., Ibanez M. A., Dhople A. A. In vitro activities of 2,2'-bipyridyl analogs against Mycobacterium leprae. Antimicrob Agents Chemother. 1994 Dec;38(12):2908–2909. doi: 10.1128/aac.38.12.2908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Eissenberg L. G., Goldman W. E., Schlesinger P. H. Histoplasma capsulatum modulates the acidification of phagolysosomes. J Exp Med. 1993 Jun 1;177(6):1605–1611. doi: 10.1084/jem.177.6.1605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gmelig-Meyling F., Waldmann T. A. Separation of human blood monocytes and lymphocytes on a continuous Percoll gradient. J Immunol Methods. 1980;33(1):1–9. doi: 10.1016/0022-1759(80)90077-0. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Hider R. C., Singh S., Porter J. B., Huehns E. R. The development of hydroxypyridin-4-ones as orally active iron chelators. Ann N Y Acad Sci. 1990;612:327–338. doi: 10.1111/j.1749-6632.1990.tb24320.x. [DOI] [PubMed] [Google Scholar]
  15. Jacobs A. Low molecular weight intracellular iron transport compounds. Blood. 1977 Sep;50(3):433–439. [PubMed] [Google Scholar]
  16. 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]
  17. Krogstad D. J., Schlesinger P. H. Acid-vesicle function, intracellular pathogens, and the action of chloroquine against Plasmodium falciparum. N Engl J Med. 1987 Aug 27;317(9):542–549. doi: 10.1056/NEJM198708273170905. [DOI] [PubMed] [Google Scholar]
  18. Lane T. E., Wu-Hsieh B. A., Howard D. H. Gamma interferon cooperates with lipopolysaccharide to activate mouse splenic macrophages to an antihistoplasma state. Infect Immun. 1993 Apr;61(4):1468–1473. doi: 10.1128/iai.61.4.1468-1473.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lane T. E., Wu-Hsieh B. A., Howard D. H. Iron limitation and the gamma interferon-mediated antihistoplasma state of murine macrophages. Infect Immun. 1991 Jul;59(7):2274–2278. doi: 10.1128/iai.59.7.2274-2278.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Laub R., Schneider Y. J., Octave J. N., Trouet A., Crichton R. R. Cellular pharmacology of deferrioxamine B and derivatives in cultured rat hepatocytes in relation to iron mobilization. Biochem Pharmacol. 1985 Apr 15;34(8):1175–1183. doi: 10.1016/0006-2952(85)90492-7. [DOI] [PubMed] [Google Scholar]
  21. Lestas A. N. The effect of pH upon human transferrin: selective labelling of the two iron-binding sites. Br J Haematol. 1976 Mar;32(3):341–350. doi: 10.1111/j.1365-2141.1976.tb00937.x. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Muller D., Edwards M. L., Smith D. W. Changes in iron and transferrin levels and body temperature in experimental airborne legionellosis. J Infect Dis. 1983 Feb;147(2):302–307. doi: 10.1093/infdis/147.2.302. [DOI] [PubMed] [Google Scholar]
  24. Neilands J. B. Microbial envelope proteins related to iron. Annu Rev Microbiol. 1982;36:285–309. doi: 10.1146/annurev.mi.36.100182.001441. [DOI] [PubMed] [Google Scholar]
  25. Neilands J. B. Microbial iron compounds. Annu Rev Biochem. 1981;50:715–731. doi: 10.1146/annurev.bi.50.070181.003435. [DOI] [PubMed] [Google Scholar]
  26. Newman S. L., Bucher C., Rhodes J., Bullock W. E. Phagocytosis of Histoplasma capsulatum yeasts and microconidia by human cultured macrophages and alveolar macrophages. Cellular cytoskeleton requirement for attachment and ingestion. J Clin Invest. 1990 Jan;85(1):223–230. doi: 10.1172/JCI114416. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Newman S. L., Gootee L., Brunner G., Deepe G. S., Jr Chloroquine induces human macrophage killing of Histoplasma capsulatum by limiting the availability of intracellular iron and is therapeutic in a murine model of histoplasmosis. J Clin Invest. 1994 Apr;93(4):1422–1429. doi: 10.1172/JCI117119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Newman S. L., Gootee L., Bucher C., Bullock W. E. Inhibition of intracellular growth of Histoplasma capsulatum yeast cells by cytokine-activated human monocytes and macrophages. Infect Immun. 1991 Feb;59(2):737–741. doi: 10.1128/iai.59.2.737-741.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Newman S. L., Gootee L. Colony-stimulating factors activate human macrophages to inhibit intracellular growth of Histoplasma capsulatum yeasts. Infect Immun. 1992 Nov;60(11):4593–4597. doi: 10.1128/iai.60.11.4593-4597.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Newman S. L., Gootee L., Morris R., Bullock W. E. Digestion of Histoplasma capsulatum yeasts by human macrophages. J Immunol. 1992 Jul 15;149(2):574–580. [PubMed] [Google Scholar]
  31. Princiotto J. V., Zapolski E. J. Difference between the two iron-binding sites of transferrin. Nature. 1975 May 1;255(5503):87–88. doi: 10.1038/255087a0. [DOI] [PubMed] [Google Scholar]
  32. SMITH R. S. Iron excretion in thalassaemia major after administration of chelating agents. Br Med J. 1962 Dec 15;2(5319):1577–1580. doi: 10.1136/bmj.2.5319.1577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Schnur R. A., Newman S. L. The respiratory burst response to Histoplasma capsulatum by human neutrophils. Evidence for intracellular trapping of superoxide anion. J Immunol. 1990 Jun 15;144(12):4765–4772. [PubMed] [Google Scholar]
  34. Seydel J. K., van der Goot H., Timmerman H. Influence of membrane composition of various parasites on the inhibitory activity of a series of bipyridyl analogues. Chemotherapy. 1994 Mar-Apr;40(2):124–135. doi: 10.1159/000239183. [DOI] [PubMed] [Google Scholar]
  35. Sibille J. C., Kondo H., Aisen P. Uptake of ferritin and iron bound to ferritin by rat hepatocytes: modulation by apotransferrin, iron chelators and chloroquine. Biochim Biophys Acta. 1989 Feb 9;1010(2):204–209. doi: 10.1016/0167-4889(89)90162-6. [DOI] [PubMed] [Google Scholar]
  36. Starke P. E., Gilbertson J. D., Farber J. L. Lysosomal origin of the ferric iron required for cell killing by hydrogen peroxide. Biochem Biophys Res Commun. 1985 Dec 17;133(2):371–379. doi: 10.1016/0006-291x(85)90916-7. [DOI] [PubMed] [Google Scholar]
  37. Swaiman K. F., Machen V. L. Chloroquine reduces neuronal and glial iron uptake. J Neurochem. 1986 Feb;46(2):652–654. doi: 10.1111/j.1471-4159.1986.tb13017.x. [DOI] [PubMed] [Google Scholar]
  38. Van Snick J. L., Masson P. L., Heremans J. F. The involvement of lactoferrin in the hyposideremia of acute inflammation. J Exp Med. 1974 Oct 1;140(4):1068–1084. doi: 10.1084/jem.140.4.1068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. 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]
  40. Worsham P. L., Goldman W. E. Quantitative plating of Histoplasma capsulatum without addition of conditioned medium or siderophores. J Med Vet Mycol. 1988 Jun;26(3):137–143. [PubMed] [Google Scholar]
  41. Wright D. G., Gallin J. I. Secretory responses of human neutrophils: exocytosis of specific (secondary) granules by human neutrophils during adherence in vitro and during exudation in vivo. J Immunol. 1979 Jul;123(1):285–294. [PubMed] [Google Scholar]
  42. Zähringer J., Baliga B. S., Munro H. N. Novel mechanism for translational control in regulation of ferritin synthesis by iron. Proc Natl Acad Sci U S A. 1976 Mar;73(3):857–861. doi: 10.1073/pnas.73.3.857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. de Zwart M. A., van der Goot H., Timmerman H. Synthesis and copper-dependent antimycoplasmal activity of 1-amino-3-(2-pyridyl)isoquinoline derivatives. 2. Amidines. J Med Chem. 1989 Feb;32(2):487–493. doi: 10.1021/jm00122a033. [DOI] [PubMed] [Google Scholar]

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