BioMetals

, 22:61 | Cite as

Utilization of microbial iron assimilation processes for the development of new antibiotics and inspiration for the design of new anticancer agents

  • Marvin J. Miller
  • Helen Zhu
  • Yanping Xu
  • Chunrui Wu
  • Andrew J. Walz
  • Anne Vergne
  • John M. Roosenberg
  • Garrett Moraski
  • Albert A. Minnick
  • Julia McKee-Dolence
  • Jingdan Hu
  • Kelley Fennell
  • E. Kurt Dolence
  • Li Dong
  • Scott Franzblau
  • Francois Malouin
  • Ute Möllmann
Article

Abstract

Pathogenic microbes rapidly develop resistance to antibiotics. To keep ahead in the “microbial war”, extensive interdisciplinary research is needed. A primary cause of drug resistance is the overuse of antibiotics that can result in alteration of microbial permeability, alteration of drug target binding sites, induction of enzymes that destroy antibiotics (ie., beta-lactamase) and even induction of efflux mechanisms. A combination of chemical syntheses, microbiological and biochemical studies demonstrate that the known critical dependence of iron assimilation by microbes for growth and virulence can be exploited for the development of new approaches to antibiotic therapy. Iron recognition and active transport relies on the biosyntheses and use of microbe-selective iron-chelating compounds called siderophores. Our studies, and those of others, demonstrate that siderophores and analogs can be used for iron transport-mediated drug delivery (“Trojan Horse” antibiotics) and induction of iron limitation/starvation (Development of new agents to block iron assimilation). Recent extensions of the use of siderophores for the development of novel potent and selective anticancer agents are also described.

Keywords

Siderophores Drug conjugates Antibiotics Mycobactins Antituberculosis agents Anticancer agents 

References

  1. Barclay R, Ratledge C (1983) Iron-binding compounds of Mycobacterium avium, M. intracellulare, M. scrofulaceum, and mycobactin-dependent M. paratuberculosis and M. avium. J Bacteriol 53:1138–1146Google Scholar
  2. Benz G (1984) Albomycine, I. Enzymatische Spaltung der Desferriform der Albomycine. Liebigs Ann Chem 1399–1407. doi:10.1002/jlac.198419840802
  3. Benz G, Schmidt D (1984) Albomycins, 4. Isolation and total synthesis of (N-5-acetyl-N-5-hydroxy-L-Ornithyl). Liebigs Ann Chem 1434–1440. doi:10.1002/jlac.198419840805
  4. Benz G, Schroder T, Kurz J, Wunsche C, Karl W, Steffens G, Pfitzner J, Schmidt D (1982) Konstitution der Desferriform der Albomycine. Angew Chem Suppl 1322–1335Google Scholar
  5. Benz G, Born L, Briedan M, Grosser R, Kurz J, Paulsen H, Sinnwell V, Weber B (1984) Albomycins, II. Absolute Konfiguration der Desferriform der Albomycine. Liebigs Ann Chem 1408–1423. doi:10.1002/jlac.198419840803
  6. Bosne-David S, Bricard L, Ramiandrasoa FDéRoussent A, Kunesh G, Andremont A (1997) Evaluation of growth promotion and inhibition from Mycobactins and nonmycobacterial Siderophores (Desferrioxamine and FR160) in Mycobacterium aurum. Antimicrob Agents Chemother 41:1837–1839PubMedGoogle Scholar
  7. Braun V, Endriß F (2007) Energy-coupled outer membrane transport proteins and regulatory proteins. Biometals 20:219–231. doi:10.1007/s10534-006-9072-5 PubMedCrossRefGoogle Scholar
  8. Braun V, Günthner K, Hantke K, Zimmermann L (1983) Intracellular activation of albomycin in Escherichia coli and Salmonella typhimurium. J Bacteriol 156:308–315PubMedGoogle Scholar
  9. Brochu A, Brochu N, Nicas TI, Parr TR, Minnick AA, Dolence EK, McKee JA, Miller MJ, Lavoie MC, Malouin F (1992) Modes of action and inhibitory activities of new siderophore-b-lactam conjugates that use specific iron uptake pathways for entry into bacteria. Antimicrob Agents Chemother 36:2166–2175PubMedGoogle Scholar
  10. Brown KA, Ratledge C (1975) The effect of p-aminosalicylate on iron transport and assimilation in Mycobacteria. Biochim Biophys Acta 385:207–220PubMedGoogle Scholar
  11. Budzikiewicz H (2004) Siderophores of the Pseudomonadaceae sensu stricto (fluorescent and non-Fluorescent Psedomonas spp.). Prog Chem Org Nat Prod 87:81–327Google Scholar
  12. Bullen JJ (1987) In: Bullen DJ, Griffiths E (eds) Iron and infection: molecular, physiological and clinical aspects, Wiley, New York, pp 1–526 Google Scholar
  13. Carpenter JGD, Moore JW (1969) Synthesis of an analogue of mycobactin. J Chem Soc 1610–1611Google Scholar
  14. Dhungana S, Miller MJ, Dong L, Ratledge C, Crumbliss AL (2003) Fe(III) chelation properties of an extracellular siderophore exochelin MN. J Am Chem Soc 125:7654–7663. doi:10.1021/ja029578u PubMedCrossRefGoogle Scholar
  15. Dolence EK, Minnick AA, Miller MJ (1990) N5-acetyl-N5-hydroxy-l-ornithine-derived siderophore-Carbacephlosporin β-Lactam conjugates: iron transport mediated drug delivery. J Med Chem 33:461–464. doi:10.1021/jm00164a001 PubMedCrossRefGoogle Scholar
  16. Dolence EK, Lin C-E, Miller MJ (1991a) Synthesis and siderophore activi ty of albomycin-like peptides derived from N5-acetyl-N5-hydroxy-l-orinithine. J Med Chem 34:956–968. doi:10.1021/jm00107a013 PubMedCrossRefGoogle Scholar
  17. Dolence EK, Minnick AA, Lin C-E, Miller MJ (1991b) Synthesis and siderophore and antibacterial activity of N5-acetyl-N5-hydroxy-l-ornithine-derived Siderophore-β-lactam conjugates: iron-transport-mediated drug delivery. J Med Chem 34:968–978. doi:10.1021/jm00107a014 PubMedCrossRefGoogle Scholar
  18. Dong L, Roosenberg JM, Miller MJ (2002) The total synthesis of deferrisalmycin B. J Am Chem Soc 124:15001–15005. doi:10.1021/ja028386w PubMedCrossRefGoogle Scholar
  19. Fennell KA, Möllmann U, Miller MJ (2008) Syntheses and biological activity of amamistatin B and analogs. J Org Chem 73:1018–1024. doi:10.1021/jo7020532 PubMedCrossRefGoogle Scholar
  20. Ferguson AD, Hofmann E, Coulton JW (1998) Siderophore-mediated Iron tansport: crystal structure of FhuA with bound lipopolysaccharide. Science 282:2215. doi:10.1126/science.282.5397.2215 PubMedCrossRefGoogle Scholar
  21. 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 295:1715–1719. doi:10.1126/science.1067313 PubMedCrossRefGoogle Scholar
  22. 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 1:219–232. doi:10.1038/nchembio706 CrossRefGoogle Scholar
  23. Floyd RA, Lewis CA (1983) Hydroxyl free-radical formation from hydrogen peroxide by ferrous iron nucleotide complexes. Biochemistry 22:2645–2649. doi:10.1021/bi00280a008 PubMedCrossRefGoogle Scholar
  24. Ghosh A, Ghosh M, Niu C, Malouin F, Möllmann U, Miller MJ (1996) Iron transport-mediated drug delivery using mixed-ligand siderophore-β-lactam conjugates. Chem Biol 3:1011–1019. doi:10.1016/S1074-5521(96)90167-2 PubMedCrossRefGoogle Scholar
  25. Graf E, Mahoney JR, Bryant RG, Eaton JW (1984) Iron-catalysed hydroxyl radical formation-stringent requirement for free iron coordination site. J Biol Chem 259:3620–3624PubMedGoogle Scholar
  26. Guerinot ML (1994) Microbial iron transport. Annu Rev Microbiol 48:743. doi:10.1146/annurev.mi.48.100194.003523 PubMedCrossRefGoogle Scholar
  27. Gutteridge JMC, Richmond R, Halliwell B (1979) Inhibition of iron-catalyzed formation of hydroxyl radicals for superoxide and lipid peroxidation by desferrioxamine. Biochem J 184:469–472PubMedGoogle Scholar
  28. Hall RM, Ratledge C (1986) Distribution and application of mycobactins for the characterization of species within the genus Rhodococcus. J Gen Microbiol 132:853–856PubMedGoogle Scholar
  29. Heinisch L, Wittmann S, Stoiber T, Berg A, Ankel-Fuchs D, Möllmann U (2002). J Med Chem 45:3032–3040. doi:10.1021/jm010546b Google Scholar
  30. Hider RC (1984) Structure and bonding, vol 58. Springer-Verlag, Berlin, p 25Google Scholar
  31. Horwitz LD (1998) Method of treatment of atherosclerosis and vascular injury by the prevention of vascular smooth muscle cell proliferation. US Patent 5786326 and Chem Abstr 129:144856pGoogle Scholar
  32. Horwitz LD, Sherman NA, Kong Y, Pike AW, Gobin J, Fennessey PV, Horwitz MA (1988) Lipophilic siderophores of Mycobacterium tuberculosis prevent cardiac reperfusion injury. Proc Natl Acad Sci USA 95:5263–5268. doi:10.1073/pnas.95.9.5263 CrossRefGoogle Scholar
  33. Horwitz LD, Horwitz MA, Gibson BW, Reeve J (1999) Use of exochelins in the preservation of organs for transplant. US Patent 5721209 and Chem Abst 130:47472yGoogle Scholar
  34. Ikeda Y, Nonaka H, Furrmai T, Onaka H, Igarashi Y (2005) Nocardimicins A, B, C, D, E and F, siderophores with Muscarinic M3 reeptor Inhibiting activity from Nocardia sp. TP-A0674. J Nat Prod 68:1061–1065PubMedCrossRefGoogle Scholar
  35. Jaynes BH, Dirlam JP, Hecker SJ (1996) Antibacterial agents. In: Bristol JA (ed) Annual reports in medicinal chemistry, vol 31. Academic Press, London, pp 121–130Google Scholar
  36. Katsu K, Kitoh K, Inoue M, Mitsuhashi S (1982) In vitro antibacterial activity of E-0702, a new semisynthetic cephalosporin. Antimicrob Agents Chemother 22:181–185PubMedGoogle Scholar
  37. Kong Y, Lesneefsky EJ, Ye J, Horwitz LD (1994) Prevention of lipid peroxidation does not prevent oxidant-induced myocardial contractile dysfunction. Am J Physiol 267:H2371–H2377PubMedGoogle Scholar
  38. Levy SB (1992) The antibiotic paradox how miracle drugs are destroying the miraclej. Plenum Press, New York, pp 1–296Google Scholar
  39. Macham LP, Ratledge C (1975) A new group of waster-soluble iron-binding compounds from Mycobacteria: the exochelins. J Gen Microbiol 89:379–382PubMedGoogle Scholar
  40. Macham LP, Ratledge C, Nocton JC (1975) Extracellular iron acquisition by Mycobacteria: role of the exochelins and evidence against the participation of mycobactin. Infect Immun 12:1242–1251PubMedGoogle Scholar
  41. Macham LP, Stephenson MC, Ratledge C (1977) Iron transport in Mycobacterium smegmatis: the isolation, purification and function of exochelin MS. J Gen Microbiol 101:41–49Google Scholar
  42. McCready KA, Ratledge C (1977) Mycobactins from Mycobacterium avium. Int J Syst Bacteriol 7:288–289Google Scholar
  43. Mckee JA, Sharma SK, Miller MJ (1991) Iron transport mediated drug delivery systems: synthesis and antibacterial activity of spermidine- and lysine-based siderophore-β-lactam conjugates. Bioconjug Chem 2:281–291PubMedCrossRefGoogle Scholar
  44. Messenger AJM, Hall RM, Ratledge C (1986) Iron uptake processes in Mycobacterium vaccae R877R, a Mycobacterium lacking mycobactin. J Gen Microbiol 132:845–852PubMedGoogle Scholar
  45. Miethke M, Marahiel MA (2007) Siderophore-based iron acquisition and pathogen control. Microbiol Mol Biol Rev 71:413–415PubMedCrossRefGoogle Scholar
  46. Miller MJ (1989) Syntheses and therapeutic potential of hydroxamic acid based siderophores and analogues. Chem Rev 89:1563–1579CrossRefGoogle Scholar
  47. Miller MJ, Malouin F (1993) Microbial iron chelators as drug delivery agents: rational design and synthesis of siderophore-drug conjugates. Acc Chem Res 26:241–249CrossRefGoogle Scholar
  48. Miller MJ, Malouin F (1994) Sjiderophore-mediated drug delivery: the design, synthesis, and study of siderophore-antibiotic and antifungal conjugates. In: Bergeron RJ, Brittenham GM (eds) The development of iron chelators for clinical use. CRC, Boca Ratonj, pp 275–306Google Scholar
  49. Miller MJ, Malouin F, Dolence EK, Gasparski CM, Ghosh M, Guzzo PR, Lotz BT, McKee JA, Minnick A, Teng M (1993) Iron transport mediated drug delivery. In: Bently PH, Ponsford R (eds) Recent advances in the chemistry of anti-infective agents, vol 119. Royal Society of Chemistry, Cambridge, pp 135–159Google Scholar
  50. Minnick AA, McKee JA, Dolence EK, Miller MJ (1992) Iron transport-mediated antibacterial activity of and development of resistance to hydroxamate and catechol siderophore-carbacephalosporin conjugates. Antimicrob Agents Chemother 36:840–850PubMedGoogle Scholar
  51. Moody DB, Yung DC, Cheng T-Y, Rosat J-P, Roura-mir C, O’Connor PB, Zajonc DM, Walz A, Miller MJ, Levery SB, Wilson IA, Costello CE, Brenner MB (2004) T cell activation by lipopeptide antigens. Science 303:527–531PubMedCrossRefGoogle Scholar
  52. Morrison NE (1995) Mycobacterium leprae iron nutrition: bacterrioferritin, mycobactin, Exochelin and inatracellular growth. Int J Lepr 63:86–91Google Scholar
  53. Murakami Y, Kato S, Nakajima M, Matsuoka M, Kawai H, Shin-Ya K, Seto H (1996) Formobactin, a novel free radical scavenging and neuronal cell protecting substance from Nocardia sp. J Antibiot 49:839–845PubMedGoogle Scholar
  54. Neilands JB, Valenta JR (1985) Iron-containing antibiotics. In: Sigel H (ed) Metal ions in biological systems, vol 19. Marcel Dekker, New York, pp 313–333Google Scholar
  55. Patel PV, Ratledge C (1973) Isolation of lipid-soluble compounds that bind ferric ions from Nocardia species. Biochem Soc Trans 1:886–888Google Scholar
  56. Paulsen H, Briedan M, Benz G (1987) Branched and chain-extended sugars. synthesis of the deferri form of the oxygen analog of delta-1-albomycin. Liebigs Ann Chem 8:565–575CrossRefGoogle Scholar
  57. Payne SM (1988) Iron and virulence in the family Enterobacteriacae. CRC Crit Rev Microbiol 16:81CrossRefGoogle Scholar
  58. Quadri LEN (2007) Strategic paradigm shifts in the antimicrobial drug discovery process of the 21st century. Infectious disorders—drug targets 7:230–237PubMedCrossRefGoogle Scholar
  59. Quadri LEN, Sello J, Keating TA, Weinreb PH, Walsh CT (1998) Identification of a Mycobacterium tuberculosis gene cluster encoding the biosynthetic enzymes for assembly of the virulence-conferring siderophore mycobactin. Chem Biol 5:631–645PubMedCrossRefGoogle Scholar
  60. Ratledge C (1971) Transport of iron by mycobactin in Mycobacterium smegmatis. Biochem Biophys Res Commun 45:856–862PubMedCrossRefGoogle Scholar
  61. Ratledge C (1984) Metabolism of iron and other metals by Mycobacteria. Microbiol Ser 15:603–627Google Scholar
  62. Ratledge C (1987) In: Winkelmann G, van der Helm D, Neilands JB (eds) Iron transport in microbes, plants, and animals. VCH Press, Weinheim, FRG, pp 207Google Scholar
  63. Ratledge C (2004) Iron, mycobacteria and tuberculosis. Tuberculosis 84:110–130PubMedCrossRefGoogle Scholar
  64. Ratledge C, Brown KA (1972) Inhibition of mycobactin formation in Mycobacterium smegmatis by p-aminosalicylate. Am Rev Resp Dis 106:774–776PubMedGoogle Scholar
  65. Ratledge C, Marshall BJ (1972) Iron transport in Mycobacterum smegmatis: the role of mycobactin. Biochim Biophys Acta 279:58–74PubMedGoogle Scholar
  66. Ratledge C, Patel PV (1976) The isolation, properties and taxonomic relevance of lipid-soluble, iron-binding compounds (the nocobactins) from Nocardia. J Gen Microbiol 93:141–152PubMedGoogle Scholar
  67. Ratledge C, Snow GA (1974) Isolation and structure of nocobactin na, a lipid-soluble iron-binding compound from Nocardia asteroids. Biochem J 139:407–413PubMedGoogle Scholar
  68. Ratledge C, Patel PV, Mundy J (1982) Iron transport in Mycobacterium smegmatis: the location of mycobactin by electron microscopy. J Gen Microbiol 128:1559–1565PubMedGoogle Scholar
  69. Rogers HJ (1987) Bacterial iron transport as a target for antibacterial agents. In: Winkelmann G, van der Helm D, Neilands JB (eds) Iron transport in microbes, plants, and animals. VCH Press, Weinheim, pp 223–233Google Scholar
  70. Roosenberg JM, Lin Y-M, Lu Y, Miller MJ (2000) Studies and syntheses of siderophore, microbial iron chelators, and analogs as potential drug delivery agents. Curr Med Chem 7(2):159–197PubMedGoogle Scholar
  71. Sharman GJ, Williams DH, Ewing DF, Ratledge C (1995a) Isolation, purification and structure of exochelin MS, the extracellular siderophore from Mycobacterium smegmatis. Biochem J 305:187–196PubMedGoogle Scholar
  72. Sharman GJ, Williams DH, Ewing DF, Ratledge C (1995b) Determination of the structure of exochelin MN, the extracellular Siderophore from Mycobacterium neoaurum. Chem & Biol 2:553–561CrossRefGoogle Scholar
  73. Snow GA (1970) Mycobactins: iron-chelating growth factors from Mycobacteria. Bacteriol Rev 34:99–125PubMedGoogle Scholar
  74. Somu RV, Wilson DJ, Bennett EM, Boshoff H, Celia L, Beck BJ, Barry CEIII, Aldrich CC (2006) Antitubercular nucleosides that inhibit siderophore biosynthesis: SAR of the glycosyl domain. J Med Chem 49:7623–7635PubMedCrossRefGoogle Scholar
  75. Stephenson MC, Ratledge C (1978) The transport of iron from ferriexochelin by Mycobacterium smegmatis. Biochem Soc Trans 6:423–425PubMedGoogle Scholar
  76. Stephenson MC, Ratledge C (1979) Iron transport in Mycobacterium smegmatis: uptake of iron from ferriexochelin. J Gen Microbiol 110:193–202PubMedGoogle Scholar
  77. Suenaga K, Kokubo S, Shinohara C, Tsuji T, Uemura D (1999) Structures of Amamistatins A and B, novel growth inhibitors of human tumor cell lines from an Actinomycete. Tetrahedron Lett 40:1945–1948CrossRefGoogle Scholar
  78. Tsukamoto M, Murooka K, Nakajima S, Abe S, Suzuki H, Hirano K, Kondo H, Kojira K, Suda H (1997) BE-32030 A, B, C, D, and E, new antitumor substances produced by Nocardia sp. A32030. J Antibiot 50:815–821PubMedGoogle Scholar
  79. Vergne AF, Walz AJ, Miller MJ (2000) Iron chelators from Mycobacteria (1954–1999) and potential therapeutic applications. Nat Prod Rep 17:99–116PubMedCrossRefGoogle Scholar
  80. Vertesy W, Aretz W, Fehlhaber H-W, Kogler H (1995) Salmycin A-D, Antibiotika aus Streptomyces violaceus, DSM 8286, mit Siderophore-Aminoglycosid-Struktur. Helv Chim Acta 78:46–60CrossRefGoogle Scholar
  81. Walling C (1975) Fenton’s reagent revisited. Acc Chem Res 8:125–131CrossRefGoogle Scholar
  82. Walz AJ, Miller MJ (2007) β-Lactams in synthesis: short syntheses of cobactin analogs. Tetrahedron Lett 48:5103–5105CrossRefGoogle Scholar
  83. Watanabe N-A, Nagasu T, Katsu K, Kitoh K (1987) E-0702, a new cephalosporin, is incorporated into Escherichia coli cells via the tonB-dependent iron transport system. Antimicrob Agents Chemother 31:497–504PubMedGoogle Scholar
  84. Wheeler PR, Ratledge C (1994) Metabolism of M. tuberculosis. In: Bloom BR (ed) Tuberculosis pathogenesis, protection, and control. American Society of Microbiology, Washington, pp 353–385Google Scholar
  85. Winkelmann G, van der Helm D, Neilands JB (1987) (eds) Iron transport in microbes, plants, and animals. VCH Press, Weinheim, FRG, pp 1–533Google Scholar
  86. Zajonc DM, Crispin MDM, Bowden TA, Young DC, Cheng T-Y, Hu J, Costello CE, Rudd PM, Dwek RA, Miller MJ, Brenner MB, Moody DB, Wilson IA (2005) Molecular mechanism of lipopeptide presentation by CD1a. Immunity 22:209–219PubMedCrossRefGoogle Scholar
  87. Zweier JL (1988) Measurement of superoxide-derived free-radicals in the reperfused heart-evidence for a free-radical mechanism of reperfusion injury. Biol Chem 263:1353–1357Google Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Marvin J. Miller
    • 1
  • Helen Zhu
    • 1
  • Yanping Xu
    • 1
  • Chunrui Wu
    • 1
  • Andrew J. Walz
    • 1
  • Anne Vergne
    • 1
  • John M. Roosenberg
    • 1
  • Garrett Moraski
    • 1
  • Albert A. Minnick
    • 1
  • Julia McKee-Dolence
    • 1
  • Jingdan Hu
    • 1
  • Kelley Fennell
    • 1
  • E. Kurt Dolence
    • 1
  • Li Dong
    • 1
  • Scott Franzblau
    • 2
  • Francois Malouin
    • 3
  • Ute Möllmann
    • 4
  1. 1.Department of Chemistry and BiochemistryUniversity of Notre DameNotre DameUSA
  2. 2.College of PharmacyUniversity of Illinois at ChicagoChicagoUSA
  3. 3.Département de BiologieUniversité de SherbrookeSherbrookeCanada
  4. 4.Leibniz Institute for Natural Product Research and Infection Biology e.V. Hans Knöll InstituteJenaGermany

Personalised recommendations