, 22:583 | Cite as

Iron trafficking as an antimicrobial target

  • Rosanne E. Frederick
  • Jeffery A. Mayfield
  • Jennifer L. DuBoisEmail author


Iron is essential for the survival of most organisms. Microbial iron acquisition depends on multiple, sometimes complex steps, many of which are not shared by higher eukaryotes. Depriving pathogenic microbes of iron is therefore a potential antimicrobial strategy. The following minireview briefly describes general elements in microbial iron uptake pathways and summarizes some of the current work aiming at their medicinal inhibition.


Iron Antibiotic Siderophore 


  1. Bray PG, Ward SA, O’Neill PM (2005) Quinolines and artemisinin: chemistry, biology and history. In: Sullivan DJ (ed) Malaria: Drugs, disease and post-genomic biology. Springer, New YorkGoogle Scholar
  2. Brickman TJ, Mcintosh MA (1992) Overexpression and purification of ferric enterobactin esterase from escherichia-coli—demonstration of enzymatic-hydrolysis of enterobactin and its iron complex. J Biol Chem 267(17):12350–12355PubMedGoogle Scholar
  3. Britigan BE, Lewis TS, McCormick ML, Wilson ME (1998) Evidence for the existence of a surface receptor(s) for ferric lactoferrin and ferric transferrin associated with the plasma membrane of the protozoan parasite Leishmania donovani. In: Spik G et al (eds) Advances in lactoferrin research. Advances in experimental medicine volume. Springer, New YorkGoogle Scholar
  4. Brundtland GH (1999) World health organization report on infectious diseases. Available for download:
  5. Bullen JJ, Rogers HJ, Spalding PB, Ward CG (2005) Iron and infection: the heart of the matter. FEMS Immunol Med Microbiol 43(3):325–330. doi: 10.1016/j.femsim.2004.11.010 PubMedCrossRefGoogle Scholar
  6. Byers BR, Arceneaux JEL (1998) Microbial iron transport: iron acquisition by pathogenic microorganisms. In: metal ions in biological systems. CRC Press, New YorkGoogle Scholar
  7. Canonne-Hergaux F, Gruenheid S, Govoni G, Gros P (1999) The Nramp1 protein and its role in resistance to infection and macrophage function. Proc Assoc Am Physicians 111(4):283–289. doi: 10.1046/j.1525-1381.1999.99236.x PubMedCrossRefGoogle Scholar
  8. Cardo D, Horan T, Andrus M, Dembinski M, Edwards J, Peavy G, Tolson J, Wagner D (2004) National nosocomial infections surveillance (NNIS) system report, January 1992—June 2004, issued October 2004. Am J Infect Control 32:470–485. doi: 10.1016/j.ajic.2004.10.001 CrossRefGoogle Scholar
  9. Cendrowski S, MacArthur W, Hanna P (2004) Bacillus anthracis requires siderophore biosynthesis for growth in macrophages and mouse virulence. Mol Microbiol 51(2):407–417. doi: 10.1046/j.1365-2958.2003.03861.x PubMedCrossRefGoogle Scholar
  10. Centers for Disease Control and Prevention (2006) Healthcare-associated infections (HAIs). Available for download at:
  11. Challis GL (2005) A widely distributed bacterial pathway for siderophore biosynthesis independent of nonribosomal peptide synthetases. Chem Bio Chem 6:601–611. doi: 10.1002/cbic.200400283 PubMedGoogle Scholar
  12. Chen Y, Chang H, Lai Y, Pan C, Tsai S, Peng H (2004) Sequencing and analysis of the large virulence plasmid pLVPK of Klebsiella pneumoniae CG43. Gene 337:189–198. doi: 10.1016/j.gene.2004.05.008 PubMedCrossRefGoogle Scholar
  13. Crosa JH, Walsh CT (2002) Genetics and assembly line enzymology of siderophore biosynthesis in bacteria. Microbiol Mol Biol Rev 66(2):223–249. doi: 10.1128/MMBR.66.2.223-249.2002 PubMedCrossRefGoogle Scholar
  14. Dale SE, Doherty-Kirby A, Lajoie G, Heinrichs DE (2004) Role of siderophore biosynthesis in virulence of Staphylococcus aureus: identification and characterization of genes involved in production of a siderophore. Infect Immun 72(1):29–37. doi: 10.1128/IAI.72.1.29-37.2004 PubMedCrossRefGoogle Scholar
  15. Dhungana S, Crumbliss AL (2005) Coordination chemistry and redox processes in siderophore-mediated iron transport. Geomicrobiol J 22(3–4):87–98. doi: 10.1080/01490450590945870 CrossRefGoogle Scholar
  16. Donadio S, Staver MJ, McAlpine JB, Swanson SJ, Katz L (1991) Modular organization of genes required for complex polyketide biosynthesis. Science 252(5006):675–679. doi: 10.1126/science.2024119 PubMedCrossRefGoogle Scholar
  17. Fast B, Kremp K, Boshart M, Steverding D (1999) Iron-dependent regulation of transferrin receptor expression in Trypanosoma brucei. Biochem J 342:691–696. doi: 10.1042/0264-6021:3420691 PubMedCrossRefGoogle Scholar
  18. Ferreras JA, Ryu JS, Di Lello F, Tan DS, Quadri LEN (2005) Small-molecule inhibition of siderophore biosynthesis in Mycobacterium tuberculosis and Yersinia pestis. Nat Chem Biol 1(1):29–32. doi: 10.1038/nchembio706 PubMedCrossRefGoogle Scholar
  19. Finking R, Neumuller A, Solsbacher J, Konz D, Kretzschmar G, Schweitzer M, Krumm T, Marahiel MA (2003) Aminoacyl adenylate substrate analogues for the inhibition of adenylation domains of nonribosomal peptide synthetases. Chem Bio Chem 4(9):903–906. doi: 10.1002/cbic.200300666 PubMedGoogle Scholar
  20. Fischbach MA, Lin HN, Liu DR, Walsh CT (2006) How pathogenic bacteria evade mammalian sabotage in the battle for iron. Nat Chem Biol 2(3):132–138. doi: 10.1038/nchembio771 PubMedCrossRefGoogle Scholar
  21. Forrest AK, Jarvest RL, Mensah LM, O’Hanlon PJ, Pope AJ, Sheppard RJ (2000) Aminoalkyl adenylate and aminoacyl sulfamate intermediate analogues differing greatly in affinity for their cognate Staphylococcus aureus aminoacyl tRNA synthetases. Bioorg Med Chem Lett 10(16):1871–1874. doi: 10.1016/S0960-894X(00)00360-7 PubMedCrossRefGoogle Scholar
  22. Gobin J, Horwitz MA (1996) Exochelins of Mycobacterium tuberculosis remove iron from human iron-binding proteins and donate iron to mycobactins in the M. tuberculosis cell wall. J Exp Med 183(4):1527–1532PubMedCrossRefGoogle Scholar
  23. 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 Biol 10(5):1033–1043Google Scholar
  24. Gold HS, Moellering RC (1996) Antimicrobial drug-resistance. N Engl J Med 335:1445–1453. doi: 10.1056/NEJM199611073351907 PubMedCrossRefGoogle Scholar
  25. Haas H, Eisendle M, Turgeon BG (2008) Siderophores in fungal physiology and virulence. Annu Rev Phytopathol 46:149–187. doi: 10.1146/annurev.phyto.45.062806.094338 PubMedCrossRefGoogle Scholar
  26. Hersman LE, Huang A, Maurice PA, Forsythe JH (2000) Siderophore production and iron reduction by Pseudomonas mendocina in response to iron deprivation. Geomicrobiol J 17:261–273. doi: 10.1080/01490450050192965 CrossRefGoogle Scholar
  27. Hissen AHT, Wan ANC, Warwas ML, Pinto LJ, Moore MM (2005) The Aspergillus fumigatus siderophore biosynthetic gene sidA, encoding L-ornithine N-5-oxygenase, is required for virulence. Infect Immun 73(9):5493–5503. doi: 10.1128/IAI.73.9.5493-5503.2005 PubMedCrossRefGoogle Scholar
  28. Holmes MA, Paulsene W, Jide X, Ratledge C, Strong RK (2005) Siderocalin (lcn 2) also binds carboxymycobactins, potentially defending against mycobacterial infections through iron sequestration. Structure 13(1):29–41PubMedCrossRefGoogle Scholar
  29. Hu JD, Miller MJ (1997) Total synthesis of a mycobactin S, a siderophore and growth promoter of Mycobacterium smegmatis, and determination of its growth inhibitory activity against Mycobacterium tuberculosis. J Am Chem Soc 119(15):3462–3468. doi: 10.1021/ja963968x CrossRefGoogle Scholar
  30. Huynh C, Andrews NW (2008) Iron acquisition within host cells and the pathogenicity of Leishmania. Cell Microbiol 10(2):293–300PubMedGoogle Scholar
  31. Johnson L (2008) Iron and siderophores in fungal-host interactions. Mycol Res 112:170–183. doi: 10.1016/j.mycres.2007.11.012 PubMedCrossRefGoogle Scholar
  32. Kammler M, Schon C, Hantke K (1993) Characterization of the ferrous iron uptake system of escherichia-coli. J Bacteriol 175(19):6212–6219PubMedGoogle Scholar
  33. Kang HY, Armstrong SK (1998) Transcriptional analysis of the Bordetella alcaligin siderophore biosynthesis operon. J Bacteriol 180(4):855–861PubMedGoogle Scholar
  34. Kleinkauf H, Döhren H (1996) A nonribosomal system of peptide biosynthesis. Eur J Biochem 236(2):335. doi: 10.1111/j.1432-1033.1996.00335.x PubMedCrossRefGoogle Scholar
  35. Ko W-C, Paterson DL, Sagnimeni AJ, Hansen DS, Von Gottberg A, Mohapatra S, Casellas JM, Goossens H, Mulazimoglu L, Trenholme G et al (2002) Community-acquired Klebsiella pneumoniae bacteremia: global differences in clinical patterns. Emerg Infect Dis 8(2):160–166PubMedCrossRefGoogle Scholar
  36. Kragl C, Schrettl M, Abt B, Sarg B, Lindner HH, Haas H (2007) EstB-mediated hydrolysis of the siderophore triacetylfusarinine C optimizes iron uptake of Aspergillus fumigatus. Eukaryot Cell 6(8):1278–1285. doi: 10.1128/EC.00066-07 PubMedCrossRefGoogle Scholar
  37. Krishnamurthy G, Vikram R, Singh SB, Patel N, Agarwal S, Mukhopadhyay G, Basu SK, Mukhopadhyay A (2005) Hemoglobin receptor in Leishmania is a hexokinase located in the flagellar pocket. J Biol Chem 280(7):5884–5891. doi: 10.1074/jbc.M411845200 PubMedCrossRefGoogle Scholar
  38. Lambalot RH, Gehring AM, Flugel RS, Zuber P, La Celle M, Marahiel MA, Reid R, Khosla C, Walsh CT (1996) A new enzyme superfamily—the phosphopantetheinyl transferases. Chem Biol 3(11):923–936. doi: 10.1016/S1074-5521(96)90181-7 PubMedCrossRefGoogle Scholar
  39. Liu XF, Theil EC (2005) Ferritins: dynamic management of biological iron and oxygen chemistry. Acc Chem Res 3:167–175. doi: 10.1021/ar0302336 CrossRefGoogle Scholar
  40. Marahiel MA, Stachelhaus T, Mootz HD (1997) Modular peptide synthetases involved in nonribosomal peptide synthesis. Chem Rev 97(7):2651–2674. doi: 10.1021/cr960029e PubMedCrossRefGoogle Scholar
  41. Matzanke BF, Anemuller S, Schunemann V, Trautwein AX, Hantke K (2004) FhuF, part of a siderophore-reductase system. Biochem NY 43(5):1386–1392. doi: 10.1021/bi0357661 CrossRefGoogle Scholar
  42. May JJ, Kessler N, Marahiel MA, Stubbs MT (2002) Crystal structure of DhbE, an archetype for aryl acid activating domains of modular nonribosomal peptide synthetases. Proc Natl Acad Sci USA 99(19):12120–12125. doi: 10.1073/pnas.182156699 PubMedCrossRefGoogle Scholar
  43. Mazmanian SK, Skaar EP, Gaspar AH, Humayun M, Gornicki P, Jelenska J, Joachmiak A, Missiakas DM, Schneewind O (2003) Passage of heme-iron across the envelope of Staphylococcus aureus. Science 299:906–909. doi: 10.1126/science.1081147 PubMedCrossRefGoogle Scholar
  44. Mazoch J, Tesarik R, Sedlacek V, Kucera I, Turanek J (2004) Isolation and biochemical characterization of two soluble iron(III) reductases from Paracoccus denitrificans. Eur J Biochem 271:553–562. doi: 10.1046/j.1432-1033.2003.03957.x PubMedCrossRefGoogle Scholar
  45. Meyer JM, Halle F (1992) Ferrisiderohore reductases of pseudomonas. purification, properties and cellular location of the Pseudomonas aeruginosa ferripyoverdine reductase. Eur J Biochem 290:613–620Google Scholar
  46. Miethke M, Marahiel MA (2007) Siderophore-based iron acquisition and pathogen control. Microbiol Mol Biol Rev 71(3):413–451. doi: 10.1128/MMBR.00012-07 PubMedCrossRefGoogle Scholar
  47. Miethke M, Bisseret P, Beckering CL, Vignard D, Eustache J, Marahiel MA (2006) Inhibition of aryl acid adenylation domains involved in bacterial siderophore synthesis. FEBS J 273(2):409–419. doi: 10.1111/j.1742-4658.2005.05077.x PubMedCrossRefGoogle Scholar
  48. Moody DB, Young DC, Cheng TY, Rosat JP, Roura-mir C, O’Connor PB, Zajonc DM, Walz A, Miller MJ, Levery SB et al (2004) T cell activation by lipopeptide antigens. Science 303(5657):527–531. doi: 10.1126/science.1089353 PubMedCrossRefGoogle Scholar
  49. Nelson AL, Barasch JM, Bunte RM, Weiser JN (2005) Bacterial colonization of nasal mucosa induces expression of siderocalin, an iron-sequestering component of innate immunity. Cell Microbiol 7(10):1404–1417. doi: 10.1111/j.1462-5822.2005.00566.x PubMedCrossRefGoogle Scholar
  50. Neres J, Labello NP, Somu RV, Boshoff HI, Wilson DJ, Vannada J, Chen L, Barry CE, Bennett EM, Aldrich CC (2008) Inhibition of siderophore biosynthesis in Mycobacterium tuberculosis with nucleoside bisubstrate analogues: structure-activity relationships of the nucleobase domain of 5 ‘-O-[N-(salicyl)sulfamoyl]adenosine. J Med Chem 51(17):5349–5370. doi: 10.1021/jm800567v PubMedCrossRefGoogle Scholar
  51. 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(5778):1399–1402. doi: 10.1126/science.1128057 PubMedCrossRefGoogle Scholar
  52. Pfeifer E, Pavela-Vrancic M, von Doehren H, Kleinkauf H (1995) Characterization of tyrocidine synthetase 1 (TY1): requirement of posttranslational modification for peptide biosynthesis. Biochemistry 34(22):7450–7459. doi: 10.1021/bi00022a019 PubMedCrossRefGoogle Scholar
  53. Philpott CC (2006) Iron uptake in fungi: a system for every source. Biochim Et Biophys Acta-Molecular Cell Res 1763(7):636–645. doi: 10.1016/j.bbamcr.2006.05.008 CrossRefGoogle Scholar
  54. Qiao C, Wilson DJ, Bennett EM, Aldrich CC (2007a) A mechanism-based aryl carrier protein/thiolation domain affinity probe. J Am Chem Soc 129(20):6350–6351. doi: 10.1021/ja069201e PubMedCrossRefGoogle Scholar
  55. Qiao CH, Gupte A, Boshoff HI, Wilson DJ, Bennett EM, Somu RV, Barry CE, Aldrich CC (2007b) 5’-O-[(N-acyl)sulfamoyl]adenosines as antitubercular agents that inhibit MbtA: an adenylation enzyme required for siderophore biosynthesis of the mycobactins. J Med Chem 50(24):6080–6094. doi: 10.1021/jm070905o PubMedCrossRefGoogle Scholar
  56. Quadri LE (2000) Assembly of aryl-capped siderophores by modular peptide synthetases and polyketide synthases. Mol Microbiol 37:1–12PubMedCrossRefGoogle Scholar
  57. Ratledge C, Dover LG (2000) Iron metabolism in pathogenic bacteria. Annu Rev Microbiol 54:881–941. doi: 10.1146/annurev.micro.54.1.881 PubMedCrossRefGoogle Scholar
  58. Roosenberg JM, Lin YM, Lu Y, Miller MJ (2000) Studies and syntheses of siderophores, microbial iron chelators, and analogs as potential drug delivery agents. Curr Med Chem 7(2):159–197PubMedGoogle Scholar
  59. Schlumbohm W, Stein T, Ullrich C, Vater J, Krause M, Marahiel M, Kruft V, Wittmann-Liebold B (1991) An active serine is involved in covalent substrate amino acid binding at each reaction center of gramicidin S synthetase. J Biol Chem 266(34):23135–23141PubMedGoogle Scholar
  60. Schrettl M, Bignell E, Kragl C, Joechl C, Rogers T, Arst HN, Haynes K, Haas H (2004) Siderophore biosynthesis but not reductive iron assimilation is essential for Aspergillus fumigates virulence. J Exp Med 200(9):1213–1219. doi: 10.1084/jem.20041242 PubMedCrossRefGoogle Scholar
  61. Schroder I, Johnson E, De Vries S (2003) Microbial ferric iron reductases. FEMS Microbiol Rev 27:427–447. doi: 10.1016/S0168-6445(03)00043-3 PubMedCrossRefGoogle Scholar
  62. Searle S, Bright NA, Roach TIA, Atkinson PGP, Barton CH, Meloen RH, Blackwell JM (1998) Localisation of Nramp1 in macrophages: modulation with activation and infection. J Cell Sci 111:2855–2866PubMedGoogle Scholar
  63. Skaar EP, Gaspar AH, Schneewind O (2004) IsdG and IsdI, heme-degrading enzymes in the cytoplasm of staphylococcus aureus. J Biol Chem 279(1):436–443. doi: 10.1074/jbc.M307952200 PubMedCrossRefGoogle Scholar
  64. Somu RV, Boshoff H, Qiao CH, Bennett EM, Barry CE, Aldrich CC (2006a) Rationally designed nucleoside antibiotics that inhibit siderophore biosynthesis of Mycobacterium tuberculosis. J Med Chem 49(1):31–44. doi: 10.1021/jm051060o PubMedCrossRefGoogle Scholar
  65. Somu RV, Wilson DJ, Bennett EM, Boshoff HI, Celia L, Beck BJ, Barry CE, Aldrich CC (2006b) Antitubercular nucleosides that inhibit siderophore biosynthesis: SAR of the glycosyl domain. J Med Chem 49(26):7623–7635. doi: 10.1021/jm061068d PubMedCrossRefGoogle Scholar
  66. Sutak R, Lesuisse E, Tachezy J, Richardson DR (2008) Crusade for iron: iron uptake in unicellular eukaryotes and its significance for virulence. Trends Microbiol 16(6):261–268. doi: 10.1016/j.tim.2008.03.005 PubMedCrossRefGoogle Scholar
  67. van Luenen H, Kieft R, Mussmann R, Engstler M, ter Riet B, Borst P (2005) Trypanosomes change their transferrin receptor expression to allow effective uptake of host transferrin. Mol Microbiol 58(1):151–165. doi: 10.1111/j.1365-2958.2005.04831.x PubMedCrossRefGoogle Scholar
  68. Vannada J, Bennett EM, Wilson DJ, Boshoff HI, Barry CE, Aldrich CC (2006) Design, synthesis, and biological evaluation of b-ketosulfanamide adenylation inhibitors as potential antitubercular agents. Org Lett 8(21):4707–4710. doi: 10.1021/ol0617289 PubMedCrossRefGoogle Scholar
  69. Vasil ML, Ochsner UA (1999) The response of Pseudomonas aeruginosa to iron: genetics, biochemistry and virulence. Mol Microbiol 34(3):399–413. doi: 10.1046/j.1365-2958.1999.01586.x PubMedCrossRefGoogle Scholar
  70. Vetting MW, de Carvalho LPS, Yu M, Hegde SS, Magnet S, Roderick SL, Blanchard JS (2005) Structure and functions of the GNAT superfamily of acetyltransferases. Arch Biochem Biophys 433(1):212–226. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  71. von Dohren H, Keller U, Vater J, Zocher R (1997) Multifunctional peptide synthetases. Chem Rev 97(7):2675–2706. doi: 10.1021/cr9600262 CrossRefGoogle Scholar
  72. Walsh CT (2000) Molecular mechanisms that confer antibacterial drug resistance. Nature 406:775–781. doi: 10.1038/35021219 PubMedCrossRefGoogle Scholar
  73. Wegele R, Tasler R, Zeng YH, Rivera M, Frankenberg-Dinkel N (2004) The heme oxygenase(s)-phytochrome system of Pseudomonas aeruginosa. J Biol Chem 279(44):45791–45802. doi: 10.1074/jbc.M408303200 PubMedCrossRefGoogle Scholar
  74. Weinberg ED (1998) Patho-ecological implications of microbial acquisition of host iron. Revs Med Microbiol 9(3):171–178Google Scholar
  75. Weinberg ED, Weinberg GA (1995) The role of iron in infection. Curr Opin Infect Dis 8(3):164–169. doi: 10.1097/00001432-199506000-00004 CrossRefGoogle Scholar
  76. WHO (2005) Global tuberculosis control: surveillance, planning, financing. WHO report 2005. Geneva, world health organization (WHO/HTM/TB/2005.349)Google Scholar
  77. Wilson ME, Lewis TS, Miller MA, McCormick ML, Britigan BE (2002) Leishmania chagasi: uptake of iron bound to lactoferrin or transferrin requires an iron reductase. Exp Parasitol 100(3):196–207. doi: 10.1016/S0014-4894(02)00018-8 PubMedCrossRefGoogle Scholar
  78. Wyllie S, Seu P, Goss JA (2002) The natural resistance-associated macrophage protein 1 Slc11a1 (formerly Nramp1) and iron metabolism in macrophages. Microbes Infect 4(3):351–359. doi: 10.1016/S1286-4579(02)01548-4 PubMedCrossRefGoogle Scholar
  79. Yang J et al (2002) Iron delivery pathway mediated by a lipocalin. Mol Cell Biol 10(5):1045–1056Google Scholar
  80. Yu VL, Hansen DS, Ko WC, Sagnimeni AJ, Klugman KP, Von Gottberg A, Goossens H, Wagener MM, Benedi VJ (2007) Virulence characteristics of Klebsiella and clinical manifestations of K. pneumoniae bloodstream infections. Emerging Infectious Diseases 13(7): available for download at

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Rosanne E. Frederick
    • 1
  • Jeffery A. Mayfield
    • 1
  • Jennifer L. DuBois
    • 1
    Email author
  1. 1.Department of Chemistry and BiochemistryUniversity of Notre DameNotre DameUSA

Personalised recommendations