, Volume 23, Issue 4, pp 601–611 | Cite as

Siderophore uptake in bacteria and the battle for iron with the host; a bird’s eye view

  • Byron C. Chu
  • Alicia Garcia-Herrero
  • Ted H. Johanson
  • Karla D. Krewulak
  • Cheryl K. Lau
  • R. Sean Peacock
  • Zoya Slavinskaya
  • Hans J. Vogel


Siderophores are biosynthetically produced and secreted by many bacteria, yeasts, fungi and plants, to scavenge for ferric iron (Fe3+). They are selective iron-chelators that have an extremely high affinity for binding this trivalent metal ion. The ferric ion is poorly soluble but it is the form of iron that is predominantly found in oxygenated environments. Siderophore uptake in bacteria has been extensively studied and over the last decade, detailed structural information for many of the proteins that are involved in their transport has become available. Specifically, numerous crystal structures for outer membrane siderophore transporters, as well as for soluble periplasmic siderophore-binding proteins, have been reported. Moreover, unique siderophore-binding proteins have recently been serendipitously discovered in humans, and the structures of some of their siderophore-complexes have been characterized. The binding pockets for different ferric-siderophores in these proteins have been described in great molecular detail. In addition to highlighting this structural information, in this review paper we will also briefly discuss the relevant chemical properties of iron, and provide a perspective on our current understanding of the human and bacterial iron uptake pathways. Potential clinical uses of siderophores will also be discussed. The emerging overall picture is that iron metabolism plays an extremely important role during bacterial infections. Because levels of free ferric iron in biological systems are always extremely low, there is serious competition for iron and for ferric-siderophores between pathogenic bacteria and the human or animal host.


Siderophore Iron transport Hepcidin TonB Host defense Siderocalin 


  1. Anderson GJ, Frazer DM, McLaren GD (2009) Iron absorption and metabolism. Curr Opin Gastroenterol 25:129–135CrossRefPubMedGoogle Scholar
  2. Baker EN, Baker HM, Kidd RD (2002) Lactoferrin and transferrin: functional variations on a common structural framework. Biochem Cell Biol 80:27–34CrossRefPubMedGoogle Scholar
  3. Barry SM, Challis GL (2009) Recent advances in siderophore biosynthesis. Curr Opin Chem Biol 13:205–215CrossRefPubMedGoogle Scholar
  4. Bernhardt PV (2007) Coordination chemistry and biology of chelators for the treatment of iron overload disorders. Dalton Trans 30:3214–3220CrossRefPubMedGoogle Scholar
  5. Bister B, Bischoff D, Nicholson GJ, Valdebenito M, Schneider K, Winkelmann G, Hantke K, Süssmuth RD (2004) The structure of salmochelins: C-glucosylated enterobactins of Salmonella enterica. Biometals 17:471–481CrossRefPubMedGoogle Scholar
  6. Braun V, Killmann H (1999) Bacterial solutions to the iron-supply problem. Trends Biochem Sci 24:104–109CrossRefPubMedGoogle Scholar
  7. Bring P, Partovi N, Ford JE, Yoshida EM (2008) Iron overload disorders: treatment options for patients refractory to or intolerant of phlebotomy. Pharmacotherapy 28:331–342CrossRefPubMedGoogle Scholar
  8. Cappellini MD, Pattoneri P (2009) Oral iron chelators. Annu Rev Med 60:25–38CrossRefPubMedGoogle Scholar
  9. Carpenter BM, Whitmire JM, Merrell DS (2009) This is not your mother’s repressor: the complex role of fur in pathogenesis. Infect Immun 77:2590–2601CrossRefPubMedGoogle Scholar
  10. Cescau S, Cwerman H, Létoffé S, Delepelaire P, Wandersman C, Biville F (2007) Heme acquisition by hemophores. Biometals 20:603–613CrossRefPubMedGoogle Scholar
  11. Chan DI, Vogel HJ (2010) Current understanding of fatty acid biosynthesis and the acyl carrier protein. Biochem J (in press)Google Scholar
  12. Chiancone E, Ceci P, Ilari A, Ribacchi F, Stefanini S (2004) Iron and proteins for iron storage and detoxification. Biometals 17:197–202CrossRefPubMedGoogle Scholar
  13. Chu BC, Peacock RS, Vogel HJ (2007) Bioinformatic analysis of the TonB protein family. Biometals 20:467–483CrossRefPubMedGoogle Scholar
  14. Clarke TE, Ku SY, Dougan DR, Vogel HJ, Tari LW (2000) The structure of the ferric siderophore binding protein FhuD complexed with gallichrome. Nat Struct Biol 7:287–289CrossRefPubMedGoogle Scholar
  15. Clarke TE, Braun V, Winkelmann G, Tari LW, Vogel HJ (2002) X-ray crystallographic structures of the Escherichia coli periplasmic protein FhuD bound to hydroxamate-type siderophores and the antibiotic albomycin. J Biol Chem 277:13966–13972CrossRefPubMedGoogle Scholar
  16. Crichton R (2009) Iron metabolism, from molecular mechanisms to clinical consequences, 3rd edn. Wiley Interscience, Chichester, West SussexGoogle Scholar
  17. Crosa JH, Walsh CT (2002) Genetics and assembly line enzymology of siderophore biosynthesis in bacteria. Microbiol Mol Biol Rev 66:223–249CrossRefPubMedGoogle Scholar
  18. Dobbin PS, Hider RC, Hall AD, Taylor PD, Sarpong P, Porter JB, Xiao G, van der Helm D (1993) 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 36:2448–2458CrossRefPubMedGoogle Scholar
  19. Ferguson AD, Chakraborty R, Smith BS, Esser L, van der Helm D, Deisenhofer J (2002) Structural basis of gating by the outer membrane transporter FecA. Science 295:1715–1719CrossRefPubMedGoogle Scholar
  20. Fischbach MA, Lin H, Liu DR, Walsh CT (2006) How pathogenic bacteria evade mammalian sabotage in the battle for iron. Nat Chem Biol 2:132–138CrossRefPubMedGoogle Scholar
  21. Fleming A (1922) On a remarkable bacteriolytic element found in tissues and secretions. Proc R Soc Lond B 93:306–317CrossRefGoogle Scholar
  22. Flo TH, Smith KD, Sato S, Rodriguez DJ, Holmes MA, Strong RK, Akira S, Aderem A (2004) Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432:917–921CrossRefPubMedGoogle Scholar
  23. Fluckinger M, Haas H, Merschak P, Glasgow BJ, Redl B (2004) Human tear lipocalin exhibits antimicrobial activity by scavenging microbial siderophores. Antimicrob Agents Chemother 48:3367–3372CrossRefPubMedGoogle Scholar
  24. Ganz T (2003) Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 102:783–788CrossRefPubMedGoogle Scholar
  25. Ganz T (2006) Hepcidin—a peptide hormone at the interface of innate immunity and iron metabolism. Curr Top Microbiol Immunol 306:183–198CrossRefPubMedGoogle Scholar
  26. Garcia-Herrero A, Peacock RS, Howard SP, Vogel HJ (2007) The solution structure of the periplasmic domain of the TonB system ExbD protein reveals an unexpected structural homology with siderophore-binding proteins. Mol Microbiol 66:872–889CrossRefPubMedGoogle Scholar
  27. Goetz DH, Holmes MA, Borregaard N, Bluhm ME, Raymond KN, Strong RK (2002) The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol Cell 10:1033–1043CrossRefPubMedGoogle Scholar
  28. Grigg JC, Cooper JD, Cheung J, Heinrichs DE, Murphy ME (2010) The Staphylococcus aureus siderophore receptor HtsA undergoes localized conformational changes to enclose staphyloferrin A in an arginine-rich binding pocket. J Biol Chem 285:11162–11171CrossRefPubMedGoogle Scholar
  29. Hantke K, Nicholson G, Rabsch W, Winkelmann G (2003) Salmochelins, siderophores of Salmonella enterica and uropathogenic Escherichia coli strains, are recognized by the outer membrane receptor IroN. Proc Natl Acad Sci USA 100:3677–3682CrossRefPubMedGoogle Scholar
  30. Harrison PM, Arosio P (1996) The ferritins: molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta 1275:161–203CrossRefPubMedGoogle Scholar
  31. Hider RC, Kong X (2010) Chemistry and biology of siderophores. Nat Prod Rep 27:637–657CrossRefPubMedGoogle Scholar
  32. Hunter HN, Fulton DB, Ganz T, Vogel HJ (2002) The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis. J Biol Chem 277:37597–37603CrossRefPubMedGoogle Scholar
  33. Jordan JB, Poppe L, Haniu M, Arvedson T, Syed R, Li V, Kohno H, Kim H, Schnier PD, Harvey TS, Miranda LP, Cheetham J, Sasu BJ (2009) Hepcidin revisited, disulfide connectivity, dynamics, and structure. J Biol Chem 284:24155–24167CrossRefPubMedGoogle Scholar
  34. Krewulak KD, Vogel HJ (2008) Structural biology of bacterial iron uptake. Biochim Biophys Acta 1778:1781–1804CrossRefPubMedGoogle Scholar
  35. Krewulak KD, Peacock RS, Vogel HJ (2004) Periplasmic binding proteins involved in bacterial iron uptake. In: Iron transport in bacteria. ASM Press, Washington, DCGoogle Scholar
  36. Lauth X, Babon JJ, Stannard JA, Singh S, Nizet V, Carlberg JM, Ostland VE, Pennington MW, Norton RS, Westerman ME (2005) Bass hepcidin synthesis, solution structure, antimicrobial activities and synergism, and in vivo hepatic response to bacterial infections. J Biol Chem 280:9272–9282CrossRefPubMedGoogle Scholar
  37. Legrand D, Pierce A, Elass E, Carpentier M, Mariller C, Mazurier J (2008) Lactoferrin structure and functions. Adv Exp Med Biol 606:163–194CrossRefPubMedGoogle Scholar
  38. Lewinson O, Lee AT, Locher KP, Rees DC (2010) A distinct mechanism for the ABC transporter BtuCD-BtuF revealed by the dynamics of complex formation. Nat Struct Mol Biol 17:332–338CrossRefPubMedGoogle Scholar
  39. Lopez CS, Peacock RS, Crosa JH, Vogel HJ (2009) Molecular characterization of the TonB2 protein from the fish pathogen Vibrio anguillarum. Biochem J 418:49–59CrossRefPubMedGoogle Scholar
  40. Matzanke BF, Anemüller S, Schünemann V, Trautwein AX, Hantke K (2004) FhuF, part of a siderophore-reductase system. Biochemistry 43:1386–1392CrossRefPubMedGoogle Scholar
  41. Miller MJ, Zhu H, Xu Y, Wu C, Walz AJ, Vergne A, Roosenberg JM, Moraski G, Minnick AA, McKee-Dolence J, Hu J, Fennell K, Kurt Dolence E, Dong L, Franzblau S, Malouin F, Möllmann U (2009) Utilization of microbial iron assimilation processes for the development of new antibiotics and inspiration for the design of new anticancer agents. Biometals 22:61–75CrossRefPubMedGoogle Scholar
  42. Neilands JB (1995) Siderophores: structure and function of microbial iron transport compounds. J Biol Chem 270:26723–26726PubMedGoogle Scholar
  43. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306:2090–2093CrossRefPubMedGoogle Scholar
  44. Nemeth E, Preza GC, Jung CL, Kaplan J, Waring AJ, Ganz T (2005) The N-terminus of hepcidin is essential for its interaction with ferroportin: structure-function study. Blood 107:328–333CrossRefPubMedGoogle Scholar
  45. Neufeld EJ (2006) Oral chelators deferasirox and deferiprone for transfusional iron overload in thalassemia major: new data, new questions. Blood 107:3436–3441CrossRefPubMedGoogle Scholar
  46. Noinaj N, Guillier M, Barnard TJ, Buchanan SK (2010) TonB-dependent transporters: regulation, structure, and function. Annu Rev Microbiol 64 (in press). doi:10.1146/annurev.micro.112408.134247
  47. Pawelek PD, Croteau N, Ng-Thow-Hing C, Khursigara CM, Moiseeva N, Allaire M, Coulton JW (2006) Structure of TonB in complex with FhuA, E. coli outer membrane receptor. Science 312:1399–1402CrossRefPubMedGoogle Scholar
  48. Peacock RS, Weljie AM, Howard PS, Price FD, Vogel HJ (2005) The solution structure of the C-terminal domain of TonB and interaction studies with TonB box peptides. J Mol Biol 345:1185–1197CrossRefGoogle Scholar
  49. Postle K, Larsen RA (2007) TonB-dependent energy transduction between outer and cytoplasmic membranes. Biometals 20:453–465CrossRefPubMedGoogle Scholar
  50. Pramanik A, Stroeher UH, Krejci J, Standish AJ, Bohn E, Paton JC, Autenrieth IB, Braun V (2007) Albomycin is an effective antibiotic, as exemplified with Yersinia enterocolitica and Streptococcus pneumoniae. Int J Med Microbiol 297:459–469CrossRefPubMedGoogle Scholar
  51. Raymond KN, Dertz EA, Kim SS (2003) Enterobactin: an archetype for microbial iron transport. Proc Natl Acad Sci USA 100:3584–3588CrossRefPubMedGoogle Scholar
  52. Singh PK, Parsak MR, Greenberg EP, Welsh MJ (2002) A component of innate immunity prevents bacterial biofilm development. Nature 417:552–555CrossRefPubMedGoogle Scholar
  53. Thomas X, Destoumieux-Garzón D, Peduzzi J, Afonso C, Blond A, Birlirakis N, Goulard C, Dubost L, Thai R, Tabet JC, Rebuffat S (2004) Siderophore peptide, a new type of post-translationally modified antibacterial peptide with potent activity. J Biol Chem 279:28233–28242CrossRefPubMedGoogle Scholar
  54. Valenti P, Antonini G (2005) Lactoferrin: an important host defence against microbial and viral attack. Cell Mol Life Sci 62:2576–2587CrossRefPubMedGoogle Scholar
  55. van der Helm D, Jalal MAF, Hossain MB (1987) The crystal structures, conformations and configurations of siderophores. In: Iron transport in bacteria, plant and animals. VCH Publishers, New YorkGoogle Scholar
  56. Weinberg ED (1984) Iron withholding: a defense against infection and neoplasia. Physiol Rev 64:65–102PubMedGoogle Scholar
  57. Yang D, Liu ZH, Tewary P, Chen Q, de la Rosa G, Oppenheim JJ (2007) Defensin participation in innate and adaptive immunity. Curr Pharm Des 13:3131–3139CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Byron C. Chu
    • 1
  • Alicia Garcia-Herrero
    • 1
  • Ted H. Johanson
    • 1
  • Karla D. Krewulak
    • 1
  • Cheryl K. Lau
    • 1
  • R. Sean Peacock
    • 1
  • Zoya Slavinskaya
    • 1
  • Hans J. Vogel
    • 1
  1. 1.Biochemistry Research Group, Department of Biological SciencesUniversity of CalgaryCalgaryCanada

Personalised recommendations