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Ironing Out the Biofilm Problem:The Role of Iron in Biofilm Formation

Chapter
Part of the Springer Series on Biofilms book series (BIOFILMS, volume 2)

Abstract

The opportunistic pathogen Pseudomonas aeruginosa causes chronic biofilm-associated infections in the lungs of cystic fibrosis patients that cannot be eradicated by antibiotics. Like most other pathogens, P. aeruginosa is under intense competition with the host for iron. Recent studies show that even when there is sufficient iron for growth, this element serves as a signal for biofilm development. Here, we summarize our knowledge of the role iron plays in P. aeruginosa biofilm development. Novel therapeutic approaches that target iron homeostasis as an antibiofilm target are also presented.

Keywords

Iron Uptake Iron Acquisition Ferric Citrate Cystic Fibrosis Lung Ferric Ammonium Citrate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Andrews SC, Robinson AK, Rodriguez-Quinones F (2003) Bacterial iron homeostasis. FEMS Microbiol Rev 27:215–237PubMedCrossRefGoogle Scholar
  2. 2.
    Banin E, Vasil ML, Greenberg EP (2005) Iron and Pseudomonas aeruginosa biofilm formation. Proc Natl Acad Sci USA 102:11076–11081PubMedCrossRefGoogle Scholar
  3. 3.
    Banin E, Brady KM, Greenberg EP (2006) Chelator-induced dispersal and killing of Pseudomonas aeruginosa cells in a biofilm. Appl Environ Microbiol 72:2064–2069PubMedCrossRefGoogle Scholar
  4. 4.
    Barclay R, Ratledge C (1986) Metal analogues of mycobactin and exochelin fail to act as effective antimycobacterial agents. Zentralbl Bakteriol Mikrobiol Hyg [A] 262:203–207Google Scholar
  5. 5.
    Basker MJ, Edmondson RA, Knott SJ, Ponsford RJ, Slocombe B, White SJ (1984) In vitro antibacterial properties of BRL 36650, a novel 6 alpha-substituted penicillin. Antimicrob Agents Chemother 26:734–740PubMedGoogle Scholar
  6. 6.
    Basker MJ, Frydrych CH, Harrington FP, Milner PH (1989) Antibacterial activity of catecholic piperacillin analogues. J Antibiot (Tokyo) 42:1328–1330Google Scholar
  7. 7.
    Beare PA, For RJ, Martin LW, Lamont IL (2003) Siderophore-mediated cell signalling in Pseudomonas aeruginosa: divergent pathways regulate virulence factor production and siderophore receptor synthesis. Mol Microbiol 47:195–207PubMedCrossRefGoogle Scholar
  8. 8.
    Beckmann C, Brittnacher M, Ernst R, Mayer-Hamblett N, Miller SI, Burns JL (2005) Use of phage display to identify potential Pseudomonas aeruginosa gene products relevant to early cystic fibrosis airway infections. Infect Immun 73:444–452PubMedCrossRefGoogle Scholar
  9. 9.
    Benz G, Schroder T, Kurz J, Winsche CKW, Steffens G (1982) Constitution of the desferriform of the albomycins d1, d2. Angew. Chem Int 21:527–528CrossRefGoogle Scholar
  10. 10.
    Berlutti F, Ajello M, Bosso P, Morea C, Petrucca A, Antonini G, Valenti P (2004) Both lactoferrin and iron influence aggregation and biofilm formation in Streptococcus mutans. Biometals 17:271–278PubMedCrossRefGoogle Scholar
  11. 11.
    Berlutti F, Morea C, Battistoni A, Sarli S, Cipriani P, Superti F, Ammendolia MG, Valenti P (2005) Iron availability influences aggregation, biofilm, adhesion and invasion of Pseudomonas aeruginosa and Burkholderia cenocepacia. Int J Immunopathol Pharmacol 18:661–670PubMedGoogle Scholar
  12. 12.
    Britigan BE, Hayek MB, Doebbeling BN, Fick RB Jr (1993) Transferrin and lactoferrin undergo proteolytic cleavage in the Pseudomonas aeruginosa-infected lungs of patients with cystic fibrosis. Infect Immun 61:5049–5055PubMedGoogle Scholar
  13. 13.
    Budzikiewicz H (2001) Siderophore-antibiotic conjugates used as trojan horses against Pseudomonas aeruginosa. Curr Top Med Chem 1:73–82PubMedCrossRefGoogle Scholar
  14. 14.
    Chen X, Stewart PS (2002) Role of electrostatic interactions in cohesion of bacterial biofilms. Appl Microbiol Biotechnol 59:718–720PubMedCrossRefGoogle Scholar
  15. 15.
    Chernish RN, Aaron SD (2003) Approach to resistant gram-negative bacterial pulmonary infections in patients with cystic fibrosis. Curr Opin Pulm Med 9:509–515PubMedCrossRefGoogle Scholar
  16. 16.
    Chugani S, Greenberg EP (2007) The influence of human respiratory epithelia on Pseudomonas aeruginosa gene expression. Microb Pathog 42:29–35PubMedCrossRefGoogle Scholar
  17. 17.
    Cornelis P, Matthijs S (2002) Diversity of siderophore-mediated iron uptake systems in fluorescent pseudomonads: not only pyoverdines. Environ Microbiol 4:787–798PubMedCrossRefGoogle Scholar
  18. 18.
    Costerton JW, Stewart PS, Greenberg EP (1999) Bacterial biofilms: a common cause of persistent infections. Science 284:1318–1322PubMedCrossRefGoogle Scholar
  19. 19.
    Davies D (2003) Understanding biofilm resistance to antibacterial Agents. Nat Rev Drug Discov 2:114–122PubMedCrossRefGoogle Scholar
  20. 20.
    De Vos D, De Chial M, Cochez C, Jansen S, Tummler B, Meyer JM, Cornelis P (2001) Study of pyoverdine type and production by Pseudomonas aeruginosa isolated from cystic fibrosis patients: prevalence of type II pyoverdine isolates and accumulation of pyoverdine-negative mutations. Arch Microbiol 175:384–388PubMedCrossRefGoogle Scholar
  21. 21.
    Dean CR, Poole K (1993) Cloning and characterization of the ferric enterobactin receptor gene (pfeA) of Pseudomonas aeruginosa. J Bacteriol 175:317–324PubMedGoogle Scholar
  22. 22.
    Ehrhardt P, Miller MG, Littlewood JM (1987) Iron deficiency in cystic fibrosis. Arch Dis Child 62:185–187PubMedCrossRefGoogle Scholar
  23. 23.
    Ernst RK, D'Argenio DA, Ichikawa JK, Bangera MG, Selgrade S, Burns JL, Hiatt P, McCoy K, Brittnacher M, Kas A, Spencer DH, Olson MV, Ramsey BW, Lory S, Miller SI (2003) Genome mosaicism is conserved but not unique in Pseudomonas aeruginosa isolates from the airways of young children with cystic fibrosis. Environ Microbiol 5:1341–1349PubMedCrossRefGoogle Scholar
  24. 24.
    Ghosh M, Miller MJ (1995) Design, synthesis, and biological evaluation of isocyanurate-based antifungal and macrolide antibiotic conjugates: iron transport-mediated drug delivery. Bioorg Med Chem 3:1519–1525PubMedCrossRefGoogle Scholar
  25. 25.
    Ghosh A, Ghosh M, Niu C, Malouin F, Moellmann U, Miller MJ (1996) Iron transport-mediated drug delivery using mixed-ligand siderophore-beta-lactam conjugates. Chem Biol 3:1011–1019PubMedCrossRefGoogle Scholar
  26. 26.
    Ghysels B, Ochsner U, Mollman U, Heinisch L, Vasil M, Cornelis P, Matthijs S (2005) The Pseudomonas aeruginosa pirA gene encodes a second receptor for ferrienterobactin and synthetic catecholate analogues. FEMS Microbiol Lett 246:167–174PubMedCrossRefGoogle Scholar
  27. 27.
    Haas B, Kraut J, Marks J, Zanker SC, Castignetti D (1991) Siderophore presence in sputa of cystic fibrosis patients. Infect Immun 59:3997–4000PubMedGoogle Scholar
  28. 29.
    Jesaitis AJ, Franklin MJ, Berglund D, Sasaki M, Lord CI, Bleazard JB, Duffy JE, Beyenal H, Lewandowski Z (2003) Compromised host defense on Pseudomonas aeruginosa biofilms: characterization of neutrophil and biofilm interactions. J Immunol 171:4329–4339PubMedGoogle Scholar
  29. 30.
    Johnson M, Cockayne A, Williams PH, Morrissey JA (2005) Iron-responsive regulation of biofilm formation in Staphylococcus aureus involves fur-dependent and fur-independent mechanisms. J Bacteriol 187:8211–8215PubMedCrossRefGoogle Scholar
  30. 31.
    Lamont IL, Beare PA, Ochsner U, Vasil AI, Vasil ML (2002) Siderophore-mediated signaling regulates virulence factor production in Pseudomonas aeruginosa. Proc Natl Acad Sci USA 99:7072–7077PubMedCrossRefGoogle Scholar
  31. 32.
    Llamas MA, Sparrius M, Kloet R, Jimenez CR, Vandenbroucke-Grauls C, Bitter W (2006) The heterologous siderophores ferrioxamine B and ferrichrome activate signaling pathways in Pseudomonas aeruginosa. J Bacteriol 188:1882–1891PubMedCrossRefGoogle Scholar
  32. 33.
    Lyczak JB, Cannon CL, Pier GB (2000) Establishment of Pseudomonas aeruginosa infection: lessons from a versatile opportunist. Microbes Infect 2:1051–1060PubMedCrossRefGoogle Scholar
  33. 34.
    Mey AR, Craig SA, Payne SM (2005) Characterization of Vibrio cholerae RyhB: the RyhB regulon and role of ryhB in biofilm formation. Infect Immun 73:5706–5719PubMedCrossRefGoogle Scholar
  34. 35.
    Moeck GS, Coulton JW (1998) TonB-dependent iron acquisition: mechanisms of siderophore-mediated active transport. Mol Microbiol 28:675–681PubMedCrossRefGoogle Scholar
  35. 36.
    Musk DJ, Banko DA, Hergenrother PJ (2005) Iron salts perturb biofilm formation and disrupt existing biofilms of Pseudomonas aeruginosa. Chem Biol 12:789–796PubMedCrossRefGoogle Scholar
  36. 37.
    Ochsner UA, Vasil AI, Vasil ML (1995) Role of the ferric uptake regulator of Pseudomonas aeruginosa in the regulation of siderophores and exotoxin A expression: purification and activity on iron-regulated promoters. J Bacteriol 177:7194–7201PubMedGoogle Scholar
  37. 38.
    Ochsner UA, Wilderman PJ, Vasil AI, Vasil ML (2002) GeneChip expression analysis of the iron starvation response in Pseudomonas aeruginosa: identification of novel pyoverdine biosynthesis genes. Mol Microbiol 45:1277–1287PubMedCrossRefGoogle Scholar
  38. 39.
    Orsi N (2004) The antimicrobial activity of lactoferrin: current status and perspectives. Biometals 17:189–196PubMedCrossRefGoogle Scholar
  39. 40.
    O'Toole GA, Kolter R (1998a) Flagellar and twitching motility are necessary for Pseudomonas aeruginosa biofilm development. Mol Microbiol 30:295–304PubMedCrossRefGoogle Scholar
  40. 41.
    O'Toole GA, Kolter R (1998b) Initiation of biofilm formation in Pseudomonas fluorescens WCS365 proceeds via multiple, convergent signaling pathways: a genetic analysis. Mol Microbiol 28:449–461PubMedCrossRefGoogle Scholar
  41. 42.
    O'Toole GA, Gibbs KA, Hager PW, Phibbs PV Jr, Kolter R (2000) The global carbon metabolism regulator Crc is a component of a signal transduction pathway required for biofilm development by Pseudomonas aeruginosa. J Bacteriol 182:425–431PubMedCrossRefGoogle Scholar
  42. 43.
    Palma M, Worgall S, Quadri LE (2003) Transcriptome analysis of the Pseudomonas aeruginosa response to iron. Arch Microbiol 180:374–379PubMedCrossRefGoogle Scholar
  43. 44.
    Parsek MR, Singh PK (2003) Bacterial biofilms: an emerging link to disease pathogenesis. Annu Rev Microbiol 57:677–701PubMedCrossRefGoogle Scholar
  44. 45.
    Plaha DS, Rogers HJ (1983) Antibacterial effect of the scandium complex of enterochelin. Studies of the mechanism of action. Biochim Biophys Acta 760:246–255PubMedGoogle Scholar
  45. 46.
    Pond MN, Morton AM, Conway SP (1996) Functional iron deficiency in adults with cystic fibrosis. Respir Med 90:409–413PubMedCrossRefGoogle Scholar
  46. 47.
    Poole K, McKay GA (2003) Iron acquisition and its control in Pseudomonas aeruginosa: many roads lead to Rome. Front Biosci 8:d661–686PubMedCrossRefGoogle Scholar
  47. 48.
    Ratledge C, Dover LG (2000) Iron metabolism in pathogenic bacteria. Annu Rev Microbiol 54:881–941PubMedCrossRefGoogle Scholar
  48. 49.
    Reid DW, Withers NJ, Francis L, Wilson JW, Kotsimbos TC (2002) Iron deficiency in cystic fibrosis: relationship to lung disease severity and chronic Pseudomonas aeruginosa infection. Chest 121:48–54PubMedCrossRefGoogle Scholar
  49. 50.
    Rogan MP, Taggart CC, Greene CM, Murphy PG, O'Neill SJ, McElvaney NG (2004) Loss of microbicidal activity and increased formation of biofilm due to decreased lactoferrin activity in patients with cystic fibrosis. J Infect Dis 190:1245–1253PubMedCrossRefGoogle Scholar
  50. 51.
    Rogers HJ, Synge C, Woods VE (1980) Antibacterial effect of scandium and indium complexes of enterochelin on Klebsiella pneumoniae. Antimicrob Agents Chemother 18:63–68PubMedGoogle Scholar
  51. 52.
    Rogers HJ, Woods VE, Synge C (1982) Antibacterial effect of the scandium and indium complexes of enterochelin on Escherichia coli. J Gen Microbiol 128:2389–2394PubMedGoogle Scholar
  52. 53.
    Rowe SM, Miller S, Sorscher EJ (2005) Cystic fibrosis. N Engl J Med 352:1992–2001PubMedCrossRefGoogle Scholar
  53. 54.
    Sauer K, Cullen MC, Rickard AH, Zeef LA, Davies DG, Gilbert P (2004) Characterization of nutrient-induced dispersion in Pseudomonas aeruginosa PAO1 biofilm. J Bacteriol 186:7312–7326PubMedCrossRefGoogle Scholar
  54. 55.
    Schaible UE, Kaufmann SH (2004) Iron and microbial infection. Nat Rev Microbiol 2:946–953PubMedCrossRefGoogle Scholar
  55. 56.
    Singh PK (2004) Iron sequestration by human lactoferrin stimulates P. aeruginosa surface motility and blocks biofilm formation. Biometals 17:267–270PubMedCrossRefGoogle Scholar
  56. 57.
    Singh PK, Schaefer AL, Parsek MR, Moninger TO, Welsh MJ, Greenberg EP (2000) Quorum-sensing signals indicate that cystic fibrosis lungs are infected with bacterial biofilms. Nature 407:762–764PubMedCrossRefGoogle Scholar
  57. 58.
    Singh PK, Parsek MR, Greenberg EP, Welsh MJ (2002) A component of innate immunity prevents bacterial biofilm development. Nature 417:552–555PubMedCrossRefGoogle Scholar
  58. 59.
    Smith EE, Sims EH, Spencer DH, Kaul R, Olson MV (2005) Evidence for diversifying selection at the pyoverdine locus of Pseudomonas aeruginosa. J Bacteriol 187:2138–2147PubMedCrossRefGoogle Scholar
  59. 60.
    Stites SW, Walters B, O'Brien-Ladner AR, Bailey K, Wesselius LJ (1998) Increased iron and ferritin content of sputum from patients with cystic fibrosis or chronic bronchitis. Chest 114:814–819PubMedCrossRefGoogle Scholar
  60. 61.
    Stites SW, Plautz MW, Bailey K, O'Brien-Ladner AR, Wesselius LJ (1999) Increased concentrations of iron and isoferritins in the lower respiratory tract of patients with stable cystic fibrosis. Am J Respir Crit Care Med 160:796–801PubMedGoogle Scholar
  61. 62.
    Stojiljkovic I, Kumar V, Srinivasan N (1999) Non-iron metalloporphyrins: potent antibacterial compounds that exploit haem/Hb uptake systems of pathogenic bacteria. Mol Microbiol 31:429–442PubMedCrossRefGoogle Scholar
  62. 63.
    Takase H, Nitanai H, Hoshino K, Otani T (2000) Impact of siderophore production on Pseudomonas aeruginosa infections in immunosuppressed mice. Infect Immun 68:1834–1839PubMedCrossRefGoogle Scholar
  63. 64.
    Tomaras AP, Dorsey CW, Edelmann RE, Actis LA (2003) Attachment to and biofilm formation on abiotic surfaces by Acinetobacter baumannii: involvement of a novel chaperone-usher pili assembly system. Microbiology 149:3473–3484PubMedCrossRefGoogle Scholar
  64. 65.
    Touati D (2000) Iron and oxidative stress in bacteria. Arch Biochem Biophys 373:1–6PubMedCrossRefGoogle Scholar
  65. 66.
    Vasil ML, Ochsner UA (1999) The response of Pseudomonas aeruginosa to iron: genetics, biochemistry and virulence. Mol Microbiol 34:399–413PubMedCrossRefGoogle Scholar
  66. 67.
    Visca P, Leoni L, Wilson MJ, Lamont IL (2002) Iron transport and regulation, cell signaling and genomics: lessons from Escherichia coli and Pseudomonas. Mol Microbiol 45:1177–1190PubMedCrossRefGoogle Scholar
  67. 68.
    Wang J, Lory S, Ramphal R, Jin S (1996) Isolation and characterization of Pseudomonas aeruginosa genes inducible by respiratory mucus derived from cystic fibrosis patients. Mol Microbiol 22:1005–1012PubMedCrossRefGoogle Scholar
  68. 69.
    Wilderman PJ, Sowa NA, FitzGerald DJ, FitzGerald PC, Gottesman S, Ochsner UA, Vasil ML (2004) Identification of tandem duplicate regulatory small RNAs in Pseudomonas aeruginosa involved in iron homeostasis. Proc Natl Acad Sci USA 101:9792–9797PubMedCrossRefGoogle Scholar
  69. 70.
    Wolz C, Hohloch K, Ocaktan A, Poole K, Evans RW, Rochel N, Albrecht-Gary AM, Abdallah MA, Doring G (1994) Iron release from transferrin by pyoverdin and elastase from Pseudomonas aeruginosa. Infect Immun 62:4021–4027PubMedGoogle Scholar
  70. 71.
    Xiao R, Kisaalita WS (1997) Iron acquisition from transferrin and lactoferrin by Pseudomonas aeruginosa pyoverdin. Microbiology 143:2509–2515PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  1. 1.Department of MicrobiologySchool of Medicine, University of WashingtonSeattleUSA
  2. 2.The Mina and Everard Goodman Facility of Life SciencesBar-Ilan UniversityRamat GanIsrael

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