Microbial Iron Uptake and the Antimicrobial Properties of the Transferrins

  • Anatoly Bezkorovainy
Part of the Biochemistry of the Elements book series (BOTE, volume 1)


Most if not all microorganisms including the fungi require ferric iron for growth, where iron concentration in the medium must be between 0.4 and 4 × 10−6 M (Weinberg, 1978). Yet, because the solubility product of ferric hydroxide, which is present at pH values of about 6 and above, is near 4 × 10−36, ferric iron concentrations in the growth medium are near 10−15 M. Moreover, many biological fluids contain one or several proteins of the transferrin class, which have association constants of around 1036 with respect to iron. Indeed, it has been said that the frequency of iron dissociation from human serum transferrin in the absence of small chelating agents or a specific biological system designed to abstract iron from this protein is one iron atom per 10,000 years (see Chapter 4). To overcome such obstacles, microorganisms have evolved the ability to synthesize small-molecular-weight chelators, which seek out iron in the environment and return it to the microorganism. Such chelators are termed siderochromes or, alternately, siderophores. It has been argued that the latter is the preferred term (Neilands, 1977), and we shall use it in this chapter.


Human Milk Iron Overload Ferric Iron Mycobacterium Smegmatis Picolinic Acid 
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  1. Baltimore, R. S., Vecchitto, J. S., and Pearson, H. A., 1978. Growth of Escherichia coli and concentration of iron in an infant feeding formula, Pediatrics 62: 1072–1073.PubMedGoogle Scholar
  2. Barry, D. M. J., and Reeve, A. W., 1977. Increased incidence of gram-negative neonatal sepsis with intramuscular iron administration, Pediatrics 60: 908–912.PubMedGoogle Scholar
  3. Becroft, D. M. O., Dix, M. R., and Former, K., 1977. Intramuscular iron-dextran and susceptibility of neonates to bacterial infections, Arch. Dis. Child. 52: 778–781.PubMedCrossRefGoogle Scholar
  4. Bennett, R. M., and Kokocinski, T., 1978. Lactoferrin content of peripheral blood cells, Br. J. Haematol. 39: 509–521.PubMedCrossRefGoogle Scholar
  5. Bezkorovainy, A., 1977. Human milk and colostrum proteins: A review, J. Dairy Sci. 60: 1023–1037.CrossRefGoogle Scholar
  6. Bobeck-Rutsaert, M. M. J. C., op den Kelder, A. M., Wiltink, W. F., Van Eijk, H. G., and Leijnse, B., 1974. Site of action of desferrioxamine in removing iron in normal and pathological conditions, Acta Haematol. 51: 151–158.PubMedCrossRefGoogle Scholar
  7. Bullen, J. J., and Armstrong, J. A., 1979. The role of lactoferrin in the bactericidal function of polymorphonuclear leukocytes, Immunology 36: 781–791.PubMedGoogle Scholar
  8. Bullen, J. J., Rogers, H. J., and Griffiths, E., 1972a. Iron binding proteins and infection, Br. J. Haematol. 23: 389–392.PubMedCrossRefGoogle Scholar
  9. Bullen, J. J., Rogers, H. J., and Leigh, L., 1972b. Iron-binding proteins in milk and resistance to Escherichia coli infection in infants, Br. Med. J. 1: 69–75.PubMedCrossRefGoogle Scholar
  10. Bullen, J. J., Rogers, H. J., and Griffiths, E., 1974. Bacterial iron metabolism in infection and immunity, in Microbial Iron Metabolism, J. B. Neilands (ed.), Academic Press, New York, pp. 517–551.Google Scholar
  11. Bullen, J. J., Rogers, H. J., and Griffiths, E., 1978. Role of iron in bacterial infection, Curr. Top. Microbiol. Immunol. 80: 1–35.PubMedCrossRefGoogle Scholar
  12. Caroline, L., Rosner, F., and Kozina, P. J., 1969. Elevated serum iron, low unbound transferrin, and candidiasis in acute leukemia, Blood 34: 441–451.PubMedGoogle Scholar
  13. Carrano, C. J., and Raymond, K. N., 1978. Coordination chemistry of microbial iron transport compounds: Rhodotorulic acid and iron uptake in Rhodotorula pilimanae, J. Bacteriol. 136: 69–74.PubMedGoogle Scholar
  14. Carroll, E. J., 1971. Bactericidal acitivity of bovine serums against coliform organisms isolated from milk of mastitic udders, udder skin, and environment, Am. J. Vet. Res. 32: 689–701.PubMedGoogle Scholar
  15. Committee on Nutrition, 1978. Relationship between iron status and incidence of infection in infancy, Pediatrics 62: 246–250.Google Scholar
  16. Cox, C. D., and Graham, R., 1979. Isolation of an iron-binding compound from Pseudomonas aeruginosa, J. Bacteriol. 137: 357–364.PubMedGoogle Scholar
  17. Cox, T. M., Mazurier, J., Spik, G., Montreuil, J., and Peters, T., 1979. Iron binding proteins and influx of iron across the duodenal brush border: Evidence for specific lactoferrin receptors in the human intestine, Biochim. Biophys. Acta 588: 120–128.PubMedCrossRefGoogle Scholar
  18. Emery, T., 1974. Biosynthesis and mechanism of action of hydroxamate-type siderochromes, in Microbial Iron Metabolism, J. B. Neilands (ed.), Academic Press, New York, pp. 107–123.Google Scholar
  19. Ernst, J. F., Bennett, R. L., and Rothfield, L. I., 1978. Constitutive expression of the iron-enterochelin and ferrichrome uptake systems in a mutant strain of Salmonella typhimurium, J. Bacteriol. 135: 928–934.PubMedGoogle Scholar
  20. Fairbanks, V. F., 1978. Chronic iron overload: New chelators and new strategies, J. Lab. Clin. Med. 92: 141–143.PubMedGoogle Scholar
  21. Fernandez-Pol, J. A. 1978. Isolation and characterization of a siderophore-like growth factor from mutants of SV40-transformed cells adapted to picolinic acid, Cell 14: 489–499.PubMedCrossRefGoogle Scholar
  22. Fernandez-Pol, J. A., Klos, D., and Donati, R. M., 1978. Iron transport in NRK cells synchronized in Gj by picolinic acid, Cell. Biol. Int. Rep. 2: 433–439.PubMedCrossRefGoogle Scholar
  23. Ganzoni, A. M., and Puschmann, M., 1977. Iron status and host defense, in Proteins of Iron Metabolism, E. B. Brown, P. Aisen, J. Fielding, and R. R. Crichton (eds.), Grune & Stratton, New York, pp. 427–432.Google Scholar
  24. Goldman, A. S., 1973. Host resistance factors in human milk, J. Pediatr. 82: 1082–1090.PubMedCrossRefGoogle Scholar
  25. Grieger, T. A., and Kluger, M. J., 1978. Fever and survival: The role of serum iron, J. Physiol. 279: 187–196.PubMedGoogle Scholar
  26. Griffiths, E., and Humphreys, J., 1977. Bacteriostatic effect of human milk and bovine colostrum on Escherichia coli: The importance of bicarbonate, Infect. Immun. 15: 396–401.PubMedGoogle Scholar
  27. Griffiths, E., and Humphreys, J., 1978. Alterations in /RNAs containing 2-methylthio-N6- (A2-isopentenyl)-adenosine during growth of enteropathogenic Escherichia coli in the presence of iron-binding proteins, Eur. J. Biochem. 82: 503–513.PubMedCrossRefGoogle Scholar
  28. Grohlich, D., Morley, C. G. D., and Bezkorovainy, A., 1979. Unpublished observations.Google Scholar
  29. Gross, R. L., andNewberne, P. M., 1980. Role of nutrition in immunologic function, Physiol. Rev. 60: 188–290.PubMedGoogle Scholar
  30. Harmon, R. J., Schanbacher, F. L., Ferguson, L. C., and Smith, K. L., 1976. Changes in lactoferrin, immunoglobulin G, bovine serum albumin, and a-lactalbumin during acute experimental and natural coliform mastitis in cows, Infect, and Immun. 13: 533–542.Google Scholar
  31. Hershko, C., 1978. Determinants of fecal and urinary iron excretion in desferrioxamine-treated rats, Blood 51: 415–423.PubMedGoogle Scholar
  32. Hershko, C., and Rachmilevitz, E. A., 1979. Mechanism of desferrioxamine-induced iron excretion in thalassemia, Br. J. Haematol. 42: 125–132.PubMedCrossRefGoogle Scholar
  33. Hershko, C., Cook, J. D., and Finch, C. A., 1973. Storage iron kinetics. III. Study of desferrioxamine by selective radioiron labels of the RE and parenchymal cells, J. Lab. Clin. Med. 81: 876–886.PubMedGoogle Scholar
  34. Hershko, C., Grady, R. W., and Cerami, A., 1978. Mechanism of iron chelation in the hypertransfused rat: Definition of two alternative pathways of iron mobilization, J. Lab. Clin. Med. 92: 144–151.PubMedGoogle Scholar
  35. Hider, R. C., Silver, J., Neilands, J. B., Morrison, I. E. G., and Rees, L. V. C., 1979. Identification of iron(II) enterobactin and its possible role in Escherichia coli iron transport, FEBS Lett. 102: 325–328.PubMedCrossRefGoogle Scholar
  36. Janzen, J. J., 1970. Economic losses resulting from mastitis. A review, J. Dairy Sci. 53: 1151–1161.PubMedCrossRefGoogle Scholar
  37. Jones, R. L., Peterson, C. M. Grady, R. W., Kumbaraci, T., and Cerami, A., 1977. Effects of iron chelators and iron overload on salmonella infection, Nature (London) 267: 63–65.CrossRefGoogle Scholar
  38. Keller–Schierlein, W., 1977. Chemistry of iron-chelating agents from microorganisms; development and characterization of desferrioxamine B, in Proceedings of Symposium on Development of Iron Chelators for Clinical Use, W. F. Anderson, and M. C. Hiller (eds.), Department of Health, Education, and Welfare Publication No. (NIH) 77–994, Washington, D.C., pp. 53–82.Google Scholar
  39. Kluger, M. J., and Rothenburg, B. A., 1979. Fever and reduced iron: Their interaction as a host defense response to bacterial infection, Science 203: 374–376.PubMedCrossRefGoogle Scholar
  40. Kochan, I., Wsynczuk, J., and McCabe, M. A., 1978. Effects of injected iron and sider-ophores on infections in normal and immune mice, Infect. Immun. 22: 560–567.PubMedGoogle Scholar
  41. Kumar, R., 1979. Mechanism of aneaemia of chronic infection-estimation of labile iron pool and interpretation of ferrokinetic data, Indian J. Med. Res. 70: 455–462.PubMedGoogle Scholar
  42. Kvach, J. T., Wiles, T. I., Mellencamp, M. W., and Kochan, I., 1977. Use of transfer-rin-iron-enterobactin complexes as the source of iron by serum exposed bacteria, Infect. Immun. 18: 439–445.PubMedGoogle Scholar
  43. Law, B. A., and Reiter, B., 1977. The isolation and bacteriostatic properties of lactoferrin from bovine milk whey, J. Dairy Res. 44: 595–599.PubMedCrossRefGoogle Scholar
  44. Leong, J., and Neilands, J., 1976. Mechanisms of siderophore iron transport in enteric bacteria, J. Bacteriol. 126: 823–830.PubMedGoogle Scholar
  45. Liu, P. V., and Shokrani, F., 1978. Biological activities of pyochelins: Iron-chelating agents of Pseudomones aeruginosa, Infect. Immun. 22: 878–890.PubMedGoogle Scholar
  46. Llinas, M., 1973. Metal-poly peptide interactions: The conformational state of iron proteins. II. The siderochromes, Struct. Bonding (Berlin) 17: 139–156.Google Scholar
  47. Macdougall, L. G., Anderson, R., McNab, G. M., and Katz, J., 1975. The immune response in iron-deficient children: Impaired cellular defense mechanisms with altered humoral components, J. Radiol. 86: 833–843.Google Scholar
  48. Macham, L. P., and Ratledge, C., 1975. A new group of water-soluble iron-binding compounds from mycobacteria: The exochelins, J. Gen. Microbiol. 89: 379–382.PubMedGoogle Scholar
  49. Macham, L. P., Ratledge, C., and Nocton, J. C., 1975. Extracellular iron acquisition by mycobacteria: Role of the exochelins and evidence against the participation of mycobactin, Infect. Immun. 12: 1242–1251.PubMedGoogle Scholar
  50. Marcelis, J. H., den Daas-Slagt, H. J., and Hoogkamp-Korstanje, J. A. A., 1978. Iron requirement and chelator production of staphlycocci. Streptococcus faecalis and enterobacteriacea, Antonie van Leeuwenhoek J. Microbiol. Serol. 44: 257–267.Google Scholar
  51. Masawe, A. E. J., Muindi, J. M., and Swai, G. B. R., 1974. Infections in iron deficiency and other types of anaemia in the tropics, Lancet 2: 314–317.PubMedCrossRefGoogle Scholar
  52. Masson, P. L., Heremans, J. F., Prognot, J. J., and Wanters, G., 1966. Immunochemical localization and bacteriostatic properties of an iron-binding protein from bronchial mucus, Thorax 21: 538–544.PubMedCrossRefGoogle Scholar
  53. Masson, P. L., Heremans, J. F., and Schonne, E., 1969. Lactoferrin, and iron-binding protein in neutrophilic leucocytes, J. Exp. Med. 130: 643–658.PubMedCrossRefGoogle Scholar
  54. McFarlane, H., Reddy, S., Adcock, K. J., Adeshina, H., Cooke, A. R., and Akene, J., 1970. Immunity, transferrin, and survival in kwashiorkor, Br. Med. J. 4: 268–270.CrossRefGoogle Scholar
  55. Miles, A. A., Khimji, P. L., and Maskell, J., 1979. The variable response of bacteria to excess ferric iron in host tissues, J. Med. Microbiol. 12: 17–28.PubMedCrossRefGoogle Scholar
  56. Neilands, J. B., 1973. Microbial iron transport compounds (siderochromes), in Inorganic Biochemistry, Vol. I, G. L. Eichhorn (ed.), Elsevier, Amsterdam, pp. 167–202.Google Scholar
  57. Neilands, J. B., 1974. Iron and its role in microbial phy siology, in Microbial Iron Metabolism, J. B. Neilands (ed.), Academic Press, New York, pp. 4–34.Google Scholar
  58. Neilands, J. B., 1977. Microbial iron transport compounds (siderophores), in Proceedings of Symposium on Development of Iron Chelators for Clinical Use, W. F. Anderson and M. C. Hiller (eds.), Department of Health, Education, and Welfare Publication No. (NIH) 77–994, Washington, D.C., pp. 5–44.Google Scholar
  59. Neilands, J. B., and Wayne, R. R., 1977. Membrane receptors for microbial iron transport compounds (siderophores), in Proteins of Iron Metabolism, E. B. Brown, P. Aisen, J. Fielding, and R. R. Crichton (eds.), Grune & Stratton, New York, pp. 365–369.Google Scholar
  60. Norcross, N. L., and Stark, D. M., 1970. Immunity to mastitis, a review, J. Dairy Sci. 53: 387–393.PubMedCrossRefGoogle Scholar
  61. Norrod, P., and Williams, R. P., 1978. Effects of iron and culture filtrates on killing of Neisseria gonorrhoeae by normal human serum, Infect. Immun. 21: 918–924.PubMedGoogle Scholar
  62. O’Brien, I. G., and Gibson, F., 1970. The structure of enterochelin and related 2, 3-dihy-droxy-N-benzoyl serine conjugates from Escherichia coli, Biochim, Biophys. Acta 215: 393–402.CrossRefGoogle Scholar
  63. Ong, S. A., Peterson, T., and Neilands, J. B., 1979. Agrobactin, a siderophore from Agro-bacterium aumefaciens, J. Biol. Chem. 254: 1860–1865.PubMedGoogle Scholar
  64. Payne, S. M., and Finkelstein, R. A., 1978a. Siderophore production by Vibrio Cholerae, Infect. Immun. 20: 310–311.PubMedGoogle Scholar
  65. Payne, S. M., and Finkelstein, R. A., 1978b. The critical role of iron in host bacterial interactions, J. Clin. Invest. 61: 1428–1440.PubMedCrossRefGoogle Scholar
  66. Pearson, H. A., and Robinson, J. E., 1976. The role of iron in host resistance, Adv. Pediatr. 23: 1–33.PubMedGoogle Scholar
  67. Perry, R. D., and Brubaker, R. R., 1979. Accumulation of iron by Yersiniae, J. Bacteriol. 137: 1290–1298.PubMedGoogle Scholar
  68. Pitt, C. G., Gupta, G., Estes, W. E., Rosenkrantz, H., Metterville, J. J., Crumbliss, A. L., Palmer, R. A., Nordquest, K. W., Sprinkle-Hardy, K. A., Whitcomb, D. R., Byers, B. R., Arceneaux, J. E. L., Gaines, C. G., and Sciortino, C. V., 1979. The selection and evaluation of new chelating agents for the treatment of iron overload, J. Pharmacol. Exp. Ther. 208: 12–18.PubMedGoogle Scholar
  69. Pollack, J. R., and Neilands, J. B., 1970. Enterobactin, an iron transport compound, Biochem. Biophys. Res. Commun. 38: 989–992.PubMedCrossRefGoogle Scholar
  70. Pugsley, A. P., and Reeves, P., 1977a. Uptake of ferrienterochelin by Escherichia coli: Energy-dependent state of uptake, J. Bacteriol. 130: 26–36.PubMedGoogle Scholar
  71. Pugsley, A. P., and Reeves, P., 1977b. The role of colicin receptors in the uptake of ferroenterochelin by Escherichia coli K-12, Biochem. Biophys. Res. Commun. 74: 903–911.PubMedCrossRefGoogle Scholar
  72. Raymond, K. N., and Carrano, C. J., 1979. Coordination chemistry and microbial iron transport, Acc. Chem. Res. 12: 183–190.CrossRefGoogle Scholar
  73. Reiter, B., 1978. Review of the progress of dairy science: Antimicrobial systems in milk, J. Dairy Res. 45: 131–147.PubMedCrossRefGoogle Scholar
  74. Rogers, H. J., Bullen, J. J., and Cushnie, G. H., 1970. Iron compounds and resistance to infection. Further experiments with Clostridium welchii type A in vivo and in vitro, Immunology 19: 521–538.PubMedGoogle Scholar
  75. Saarinen, U. M., Siimes, M. A., and Dallman, P. R., 1977. Iron absorption in infants: High bioavailability of breast milk iron as indicated by the extrinsic tag method of iron absorption and by the concentration of serum ferritin, J. Pediatr. 91: 36–39.PubMedCrossRefGoogle Scholar
  76. Shiraishi, A., and Arai, T., 1979. Antifungal activity of transferrin, Sabouraudia 17: 79–83.PubMedCrossRefGoogle Scholar
  77. Snow, G. A., 1970. Mycobactins: Iron-chelating growth factors from mycobacteria, Bacteriol. Rev. 34: 99–125.PubMedGoogle Scholar
  78. Spik, G., Cheron, A., Montreuil, J., and Dolby, J. M., 1978. Bacteriostasis of a milk sensitive strain of Escherichia coli by immunoglobulins and iron-binding proteins in association, Immunology 35: 663–671.PubMedGoogle Scholar
  79. Stephenson, M., and Ratledge, C., 1979. Iron transport in Mycobacterium smegmatis: Uptake of iron from ferriexochelin, J. Gen. Microbiol. 110: 193–202.PubMedGoogle Scholar
  80. Strauss, R. G., 1978. Iron deficiency, infections, and immune function: A reassessment, Am. J. Clin. Nutr. 31: 660–666.PubMedGoogle Scholar
  81. Tait, G. H., 1975. The identification and biosynthesis of siderochromes formed by Micrococcus denitrificans, Biochem. J. 146: 191–204.PubMedGoogle Scholar
  82. Van Snick, J. L., Masson, P. L., and Heremans, J. F., 1974. The involvement of lactoferrin in the hyposideremia of acute inflammation, J. Exptl. Med. 140: 1068–1084.CrossRefGoogle Scholar
  83. Waxman, H. S., and Brown, E. B., 1969. Clinical usefulness of iron chelating agents, Prog. Hematol. 6: 338–373.PubMedGoogle Scholar
  84. Wayne, R., and Neilands, J. B., 1975. Evidence for common binding sites for ferrichrome compounds and bacteriophage 80 in the cell envelope of Escherichia coli, J. Bacteriol. 121: 497–503.PubMedGoogle Scholar
  85. Weinberg, E. D., 1974. Iron and susceptibility to infectious disease, Science 184: 952–956.PubMedCrossRefGoogle Scholar
  86. Weinberg, E. D., 1977. Infection and iron metabolism, Am. J. Clin. Nutr. 30: 1485–1490.PubMedGoogle Scholar
  87. Weinberg, E. D., 1978, Iron and infection, Microbiol. Rev. 42: 45–66.PubMedGoogle Scholar
  88. Welsh, J. K., and May, J. T., 1979. Anti-infective properties of breast milk, J. of Pediatr. 94: 1–9.CrossRefGoogle Scholar
  89. Wiebe, C., and Winkelmann, G., 1975. Kinetic studies on the specificity of chelate-iron uptake in Aspergillus, J. Bacteriol. 123: 837–842.PubMedGoogle Scholar
  90. Winkelmann, G., 1979. Evidence for stereospecific uptake of iron chelates in fungi, FEBS Lett. 97: 43–46.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1980

Authors and Affiliations

  • Anatoly Bezkorovainy
    • 1
  1. 1.Rush-Presbyterian-St. Luke’s Medical CenterChicagoUSA

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