Skip to main content
SpringerLink
Log in

Iron as a candidate in virulence and pathogenesis in mycobacteria and other microorganisms

  • Published:
World Journal of Microbiology and Biotechnology Aims and scope Submit manuscript

Abstract

Iron acquisition is one of the important virulence characteristics of a pathogen. Microorganisms elaborate different ways of acquiring iron. Siderophore-mediated iron acquisition is common in many microorganisms, while some like Neisseriae directly acquire iron from the host proteins. Microorganisms also elaborate systems for iron acquisition from ferric citrate and xenosiderophores. Such modes of uptake are also seen in mycobacteria. The siderophores produced by mycobacteria are well characterised. Iron-regulated envelope proteins (IREPs) are expressed in both saprophytic and pathogenic mycobacteria. In many bacterial systems, like that of Corynebacterium diphtheriae, low iron conditions favour the expression of virulence factors. The siderophore mycobactin has been recently implicated as a virulence factor in Mycobacterium tuberculosis. The role of the IdeR repressor in controlling the expression of the iron acquisition machinery was studied with the generation of the IdeR mutant. Development of other such mutants will facilitate the study of these mechanisms in greater detail and help to develop new drugs for combating tuberculosis and leprosy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Agiato, L.A. & Dyer, D.W. 1992 Siderophore production and membrane alterations in Bordetella pertussis in response to iron starvation. Infection and Immunity 60, 117-123.

    CAS  Google Scholar 

  • Aisen, P. & Leibman, A. 1972 Lactoferrin and transferrin: a comparative study. Biochimica et Biophysica Acta 257, 314-323.

    CAS  Google Scholar 

  • Barclay, R., Furst, V. & Smith, I. 1992 A simple and rapid method for the detection and identification of mycobacteria using mycobactin. Journal of Medical Microbiology 37, 286-290.

    CAS  Google Scholar 

  • Bosne, S. & Levy-Frebault, V.V. 1992 Mycobactin analysis as an aid for the identification of Mycobacterium fortuitum and M. chelonae subspecies. Journal of Clinical Microbiology 30, 1225-1231.

    CAS  Google Scholar 

  • Bloom, B.R. & Fine, P.E.M. 1994 The BCG experience: implications for future vaccines against tuberculosis. In Tuberculosis: Pathogenesis, Protection, and Control, ed. Bloom, B.R., pp. 531-558. Washington, DC: American Society for Microbiology. ISBN 1-55581-072-1.

    Google Scholar 

  • Brooks, B.W., Young, N.M., Watson, D.C., Robertson, R.H., Sugden, E., Nielsen, K.H. & Becker, S.A. 1991 Mycobacterium paratuberculosis antigen D: characterization and evidence that it is a bacterioferritin. Journal of Clinical Microbiology 29, 1652.

    CAS  Google Scholar 

  • Braun, V., Hantke, K. & Koster, W. 1998 Bacterial iron transport: mechanisms, genetics and regulation. In Metal Ions in Biological systems. Iron Transport and Storage in Microorganisms, Plants and Animals, eds. Sigel, A. & Sigel, H., pp. 67-145. New York: Marcel Dekker. ISBN 0-8247-9984-4.

    Google Scholar 

  • Brown, M.R.W. & Williams, P. 1985 The influence of environment on envelope proteins a.ecting survival of bacteria in infections. Annual Review of Microbiology 39, 527-556.

    Article  CAS  Google Scholar 

  • Brubaker, R.R. 1985 Mechanism of bacterial virulence. Annual Review of Microbiology 39, 21-50.

    Article  CAS  Google Scholar 

  • Bullen, J.J. & Griffiths, E. (eds) 1999 Iron and Infection: Molecular, Physiological and Clinical Aspects. 2nd edition, pp. 515. Chichester, UK: John Wiley & Sons, ISBN 0-471-93940-4.

    Google Scholar 

  • Chasteen, N.D. 1998 Ferritin: uptake, storage and release of iron. In Metal Ions in Biological Systems: Iron Transport and Storage in Microorganisms, Plants and Animals, eds. Sigel, A. & Sigel, H. vol. 35. pp. 479-514. New York: Marcel Dekker Inc. ISBN 0-82479984-4.

    Google Scholar 

  • Cole, S.T. et al. 1998 Deciphering the biology of Mycobacterium tuberculosis from the complete sequence. Nature 393, 537-544.

    Article  CAS  Google Scholar 

  • Connell, T.D., Dickenson, A., Martone, A.J., Militello, K.T., Filiatraut, M.J., Hayman, M.L. & Pitula, J. 1998 Iron starvation of Bordetella avium stimulates expression of five outer membrane proteins and regulates a gene involved in acquiring iron from serum. Infection and Immunity 66, 3597-605.

    CAS  Google Scholar 

  • Courcol, R.J., Trivier, D., Bissinger, M.C., Martin, G.R. & Brown, M.R. 1997 Siderophore production by Staphylococcus aureus and identification of iron-regulated proteins Infection and Immunity 65, 1944-8.

    CAS  Google Scholar 

  • De Voss, J.J., Rutter, K., Schroeder, B.G. & Barry III, C.E. 1999 Iron acquisition and metabolism by mycobacteria. Journal of Bacteriology 181, 4443-4451.

    CAS  Google Scholar 

  • De Voss, J.J., Rutter, K., Schroeder, B.G., Su, H., Zhu, Y. & Barry III, C.E. 2000 The salicylate-derived mycobactin siderophores of Mycobacterium tuberculosis are essential for growth in macrophages. Proceedings of the National Academy of Sciences of the USA 97, 1252-1257.

    Article  CAS  Google Scholar 

  • Dhople, A.M., Ibanez, M.A. & Poirer, T.C. 1996 Role of iron in the pathogenesis of Mycobacterium avium infection in mice. Microbios 87, 77-87.

    CAS  Google Scholar 

  • Doukhan, L., Predich, M., Nair, G., Dussurget, O., Mandic-Mulec, I., Cole, S.T., Smith, D.R. & Smith, I. 1995 Genomic organization of the mycobacterial sigma gene clusters. Gene 165, 67-70.

    Article  CAS  Google Scholar 

  • Douvas, G.S., May, M.H. & Crowle, A.J. 1993 Transferrin, iron, and serum lipids enhance or inhibit Mycobacterium avium replication in human macrophages. Journal of Infectious Diseases 167, 857-864.

    CAS  Google Scholar 

  • Dover, L.G. & Ratledge, C. 1996 Identification of a 29 kDa protein in the envelope of Mycobacterium smegmatis as a putative ferriexochelin receptor. Microbiology 142, 1521-1530.

    CAS  Google Scholar 

  • Dussurget, O., Rodriguez, M. & Smith, I. 1996 An ideR mutant of Mycobacterium smegmatis has derepressed siderophore production and an altered oxidative stress response. Molecular Microbiology 22, 535-544.

    Article  CAS  Google Scholar 

  • Dussurget, O. & Smith, I. 1998 Interdependence of mycobacterial iron regulation, oxidative-stress response and isoniazid resistance. Trends in Microbiology 6, 354-358.

    Article  CAS  Google Scholar 

  • Expert, D., Enard, C. & Masclaux, C. 1996 The role of iron in plant host-pathogen interactions. Trends in Microbiology 4, 232-236.

    Article  CAS  Google Scholar 

  • Fiss, E.H., Yu, S.Y. & Jacobs, W.R. 1994 Identification of genes involved in the sequestration of iron in mycobacteria: the ferric exochelin biosynthetic and uptake pathways. Molecular Microbiology 14, 557-569.

    Article  CAS  Google Scholar 

  • Francis, J., Madinaveita, J., Macturk, H.M. & Snow, G.A. 1949 Isolation from acid-fast bacteria of a growth factor for Mycobacterium johnei and a precursor of phthicol. Nature 163, 365.

    CAS  Google Scholar 

  • Genco, C.A. & Desai, P.J. 1996 Iron acquisition in the pathogenic Neisseria. Trends in Microbiology 4, 179.

    Article  CAS  Google Scholar 

  • Gobin, J., Moore, C.H., Reeve, J.R., Wong, D.K., Gibson, B.W. & Horwitz, M.A. 1995 Iron acquisition by Mycobacterium tuberculosis: isolation and characterization of a family of iron-binding exochelins. Proceedings of the National Academy of Sciences of the USA 92, 5189-5193.

    Article  CAS  Google Scholar 

  • Gobin, J., Wong, D.K., Gibson, B.W. & Horwitz, M.A. 1999 Characterization of exochelins of the Mycobacterium bovis Type strain and BCG substrains. Infection and Immunity 67, 2035-2039.

    CAS  Google Scholar 

  • Guerinot, M.L. 1994 Microbial iron transport. Annual Review of Microbiology 48, 43-72.

    Article  Google Scholar 

  • Hall, R.M. & Ratledge, C. 1984 Mycobactins as chemotaxonomic characters for some rapidly growing mycobacteria. Journal of General Microbiology 130, 1883-1892.

    CAS  Google Scholar 

  • Hall, R.M. & Ratledge, C. 1987 Exochelin-mediated iron acquisition by the leprosy bacillus, Mycobacterium leprae. Journal of General Microbiology 133, 193-199.

    CAS  Google Scholar 

  • Hall, R.M., Sritharan, M., Messenger, A.J.M. & Ratledge, C. 1987 Iron transport in Mycobacterium smegmatis: occurrence of iron-regulated envelope proteins as potential receptors for iron uptake. Journal of General Microbiology 133, 2107-2114.

    CAS  Google Scholar 

  • Homuth, M., Valentin-Weigand, P., Rohle, M. & Gerlach, G.F. 1998 Identification and characterization of a novel extracellular ferric reductase from Mycobacterium paratuberculosis. Infection and Immunity 66, 710-716.

    CAS  Google Scholar 

  • Hu, J. & Miller, M.J. 1997 Total synthesis of mycobactin S, a siderophore and growth promoter of Mycobacterium smegmatis and determination of its growth inhibitory activity against M. tuberculosis. Journal of the American Chemical Society 119, 3462-3468.

    Article  CAS  Google Scholar 

  • Inglis, N.F., Stevenson, K., Hosie, A.H. & Sharp, J.M. 1994 Complete sequence of the gene encoding the bacterioferritin subunit of Mycobacterium avium subspecies silvaticum. Gene 150, 205-206.

    Article  CAS  Google Scholar 

  • Kochan, I. 1976 Role of iron in the regulation of nutritional immunity. Bioorganic Chemistry 2, 55-57.

    Google Scholar 

  • Koebnik, R., Locher, K.P. & van Gelder, P. 2000 Structure and function of bacterial outer membrane proteins: barrels in a nutshell. Molecular Microbiology 37, 239-253.

    Article  CAS  Google Scholar 

  • Lambrecht, R.S. & Collins, M.T. 1993 Inability to detect mycobactin in mycobacteria-infected tissues suggests an alternative iron acquisition mechanism by mycobacteria in vivo. Microbial Pathogenesis 14, 229-238.

    Article  CAS  Google Scholar 

  • Lane, S.J., Marshall, P.S., Upton, R.J. & Ratledge, C. 1998 Isolation and characterization of carboxymycobactins as the second extra-cellular siderophores in Mycobacterium smegmatis. BioMetals 11, 13-20.

    Article  CAS  Google Scholar 

  • Lane, S.J., Marshall, P.S., Upton, R.J., Ratledge, C. & Ewing, M. 1995 Novel extracellular mycobactins, the carboxymycobactins from Mycobacterium avium. Tetrahedron Letters 36, 4129-4132.

    Article  CAS  Google Scholar 

  • Litwin, C.M. & Byrne, B.L. 1998 Cloning and characterisation of an outer membrane protein of Vibrio vulnificus required for haeme utilisation: regulator of expression and determination of the gene sequence. Infection and Immunity 66, 3134-3141.

    CAS  Google Scholar 

  • Lucier, T.S., Fetherston, J.D., Brubaker, R.R. & Perry, R.D. 1996 Iron uptake and iron-repressible polypeptides in Yersinia pestis. Infection and Immunity 64, 3023-3031.

    CAS  Google Scholar 

  • Macham, L.P. & Ratledge, C. 1975 A new group of water-soluble iron binding compounds from mycobacteria: the exochelin. Journal of General Microbiology 89, 379-382.

    CAS  Google Scholar 

  • Macham, L.P., Ratledge, C. & Nocton, J.C. 1975 Extracellular iron acquisition by mycobacteria: role of the exochelins and evidence against the participation of mycobactin. Infection and Immunity 12, 1242-1251.

    CAS  Google Scholar 

  • Macham, L.P., Stephenson, M.C. & Ratledge, C. 1977 Iron transport in Mycobacterium smegmatis: the isolation, purification and function of exochelin MS. Journal of General Microbiology 101, 41-49.

    CAS  Google Scholar 

  • Manabe, Y.C., Saviola, B.J., Sun, L., Murphy, J.R. & Bishai, W.R. 1999 Attenuation of virulence in Mycobacterium tuberculosis expressing a constitutively active iron repressor. Proceedings of the National Academy of Sciences of the USA 96, 12,844-12,848.

    Article  CAS  Google Scholar 

  • Matzanke, B.F., Böhnke, R., Möllmann, U., Reissbrodt, R., Schünemann, V. & Trautwein, A.X. 1997 Iron uptake and intracellular metal transfer in mycobacteria mediated by xenosiderophores. BioMetals 10, 193-203.

    Article  CAS  Google Scholar 

  • Matzanke, B.F., Böhnke, R., Möllmann, U., Schünemann, V., Schumann, G., Trautwein, A.X. & Winklemann, G. 1999 Transport and utilisation of rhizoferrin bound iron in Mycobacterium smegmatis. BioMetals 12, 315-321.

    Article  CAS  Google Scholar 

  • Messenger, A.J.M., Hall, R.M. & Ratledge, C. 1986 Iron uptake processes in Mycobacterium vaccae R877R, a mycobacterium lacking mycobactin. Journal of General Microbiology 132, 845-852.

    CAS  Google Scholar 

  • Miller, M.J. 1989 Syntheses and therapeutic potential of hydroxamic acid based siderophores and analogues. Chemical Reviews 89, 1563-1579.

    Article  CAS  Google Scholar 

  • Miller, M.J. & Malouin, F. 1993 Microbial iron chelators as drug delivery agents: the rational design and synthesis of siderophore-drug conjugates. Accounts in Chemical Research 26, 241-249.

    Article  CAS  Google Scholar 

  • Neilands, J.B. 1990 Molecular biology and regulation of iron acquisition by Escherichia coli K12. In Molecular Basis of Bacterial Pathogenesis, eds. Iglewski, B.H. & Clark, V.L., pp. 205-223. San Diego: California Academic Press. ISBN 0-12-370390-5.

    Google Scholar 

  • Neilands, J.B. 1995 Siderophores: structure and function of microbial iron transport compounds. Journal of Biological Chemistry 270, 26,723-26,726.

    CAS  Google Scholar 

  • Neilands, J.B. 1994 Effects of iron deprivation on outer membrane protein expression. Methods in Enzymology 235, 344-352.

    Article  CAS  Google Scholar 

  • Owen, S.D.G. & Schryvers, A.B. 1996 Bacterial transferrin and lactoferrin receptors. Trends in Microbiology 4, 185-190.

    Article  Google Scholar 

  • Payne, S.M. & Lawlor, K.M. 1990 Molecular studies on iron acquisition by non-Escherichia coli species. In Molecular Basis of Bacterial Pathogenesis, ed. Iglewski, B.H. & Clark, V.L., pp. 225-248. San Diego: California Academic Press. ISBN 0-12-370390-5.

    Google Scholar 

  • Pessolani, M.C.V., Smith, D.R., Rivoire, B., McCormick, J., Hefton, S.A., Cole, S.T. & Brennan, P.J. 1994 Purification, characterization, gene sequence, and significance of a bacterioferritin from Mycobacterium leprae. Journal of Experimental Medicine 180, 319-327.

    Article  CAS  Google Scholar 

  • Pohl, E., Holmes, R.K. & Hol, W.G.J. 1999 Crystal structure of the iron-dependant Regulator (IdeR) from Mycobacterium tuberculosis shows both metal binding sites fully occupied. Journal of Molecular Biology 285, 1145-1156.

    Article  CAS  Google Scholar 

  • Portaels, F., DeRidder, K. & Pattyn, S.R. 1985 Cultivatable myco-bacteria isolated from organs of armadillo uninoculated and inoculated with Mycobacterium leprae. Annals of Microbiology (Inst. Pasteur) 136A, 181-190.

    Article  CAS  Google Scholar 

  • Quadri, L.E.N., Sello, J., Keating, T.A., Weinreb, P.H. & Walsh, C.T. 1998 Identification of a Mycobacterium tuberculosis gene cluster encoding the biosynthetic enzymes for assembly of the virulence-conferring siderophore mycobactin. Chemistry and Biology 5, 631-645.

    Article  CAS  Google Scholar 

  • Rakin, A., Sakem, E., Harmsen, D. & Heesemann, J. 1994 The pesticin receptor of Yersinia enterocolitica: a novel virulence factor with dual function. Molecular Microbiology 13, 253-263.

    Article  CAS  Google Scholar 

  • Ratledge, C. & Dover, L.G. 2000 Iron metabolism in pathogenic bacteria. Annual Review of Microbiology 54, 881-941.

    Article  CAS  Google Scholar 

  • Ratledge, C. & Ewing, M. 1996 The occurrence of carboxymycobactin, the siderophore of pathogenic mycobacteria, as a second extracellular siderophore in Mycobacterium smegmatis. Microbiology 142, 2207-2212.

    Article  CAS  Google Scholar 

  • Ratledge, C. 1999 Iron Metabolism. In Mycobacteria: Molecular Biology and Virulence, ed. Ratledge, C. & Dale, J., pp. 260-287. Oxford: Blackwell Science. ISBN 0-632-05304-6.

    Google Scholar 

  • Salyers, A.A. & Whitt, D.D. 1994 In Bacterial Pathogenesis: A Molecular Approach. New York: ASM Press. ISBN 1-55581-070-5.

    Google Scholar 

  • Sansom, M.S.P. 1999 Membrane proteins: a tale of barrels and corks. Current Biology: 9, R254-R257.

    Article  CAS  Google Scholar 

  • Schmitt, M.P., Predich, M., Doukhan, L., Smith, I. & Holmes, R.K. 1995 Characterisation of an iron-dependent regulatory protein (IdeR) of Mycobacterium tuberculosis as a functional homologue of the diphtheria toxin repressor (DtxR) from Corynebacterium diphtheriae. Infection and Immunity 63, 4284-4289.

    CAS  Google Scholar 

  • Sharman, G.J., Williams, D.H., Ewing, D.F. & Ratledge, C. 1995a Isolation, purification and structure of exochelin MS, the extra-cellular siderohore from Mycobacterium smegmatis. Biochemical Journal 305, 187-196.

    CAS  Google Scholar 

  • Sharman, G.J., Williams, D.H., Ewing, D.F. & Ratledge, C. 1995b Determination of the structure of exochelin MN, the extracellular siderophore from Mycobacterium neoaurum. Chemistry and Biology 2, 553-561.

    Article  CAS  Google Scholar 

  • Snow, G.A. 1970 Mycobactins: iron-chelating growth factors from mycobacteria. Bacteriological Reviews 34, 99-125.

    CAS  Google Scholar 

  • Sritharan, M. & Ratledge, C. 1989 Co-ordinated expression of the components of iron transport (mycobactin, exochelin and envelope proteins) in Mycobacterium neoaurum. FEMSMicrobiology Letters 60, 183-186.

    Article  CAS  Google Scholar 

  • Sritharan, M. & Ratledge, C. 1990 Iron-regulated envelope proteins of mycobacteria grown in vitro and their occurrence in Mycobacterium leprae grown in vivo. Biology of Metals 2, 203-208.

    Article  CAS  Google Scholar 

  • Tabatabai, L.B. & Frank, G.H. 1997 Purification and characterization of a 31-kilodalton iron-regulated periplasmic protein from Pasteurella haemolytica A1. Preparative Biochemistry and Biotechnology 27, 253-269.

    CAS  Google Scholar 

  • Tadepalli, A., Ayling, P.D. & Ratledge, C. 2000 Mutational analysis of a role for salicylic acid in iron metabolism of Mycobacterium smegmatis. Journal of Bacteriology 182, 264-271.

    Article  Google Scholar 

  • van Vliet, A.H.M., Wooldridge, K.G. & Ketley, J.M. 1998 Iron-responsive gene regulation in a Campylobacter jejuni fur mutant. Journal of Bacteriology 180, 5291-5298.

    CAS  Google Scholar 

  • Winklemann, G. & Drechsel, H. 1997 Microbial siderophores. In Biotechnology: Products of secondary metabolism, ed. Rehm, H.-J. & Reed, G., vol. 7, pp. 179-246. Weinheim: VCH Publishers. ISBN 3-52728317-X.

    Google Scholar 

  • Wong, D.K., Gobin, J., Horwitz, M.A. & Gibson, B.W. 1996 Characterization of exochelins of Mycobacterium avium: evidence for saturated and unsaturated acid for acid and ester forms. Journal of Bacteriology 178, 6394-6398.

    CAS  Google Scholar 

  • Xu, Y. & Miller, M. 1998 Total synthesis of mycobactin analogues as potent antimycobacterial agents using a minimal protecting group strategy. Journal of Organic Chemistry 63, 4314-4322.

    Article  CAS  Google Scholar 

  • Zhu, W., Arceneaux, J.E.L., Beggs, M.L., Byers, R.B., Eisenach, K. & Lundrigan, M.D. 1998 Exochelin genes in Mycobacterium smegmatis: identification of an ABC transporter and two non-ribosomal peptide synthetase genes. Molecular Microbiology 29, 629-639.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Animal Sciences, School of Life Sciences, University of Hyderabad, Hyderabad, 500 046, India

    Manjula Sritharan

Authors
  1. Manjula Sritharan
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sritharan, M. Iron as a candidate in virulence and pathogenesis in mycobacteria and other microorganisms. World Journal of Microbiology and Biotechnology 16, 769–780 (2000). https://doi.org/10.1023/A:1008995313232

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1008995313232

Search

Navigation