Advertisement

BioMetals

, 22:633 | Cite as

Is drug release necessary for antimicrobial activity of siderophore-drug conjugates? Syntheses and biological studies of the naturally occurring salmycin “Trojan Horse” antibiotics and synthetic desferridanoxamine-antibiotic conjugates

  • Timothy A. Wencewicz
  • Ute Möllmann
  • Timothy E. Long
  • Marvin J. MillerEmail author
Article

Abstract

The recent rise in drug resistance found amongst community acquired infections has sparked renewed interest in developing antimicrobial agents that target resistant organisms and limit the natural selection of immune variants. Recent discoveries have shown that iron uptake systems in bacteria and fungi are suitable targets for developing such therapeutic agents. The use of siderophore-drug conjugates as “Trojan Horse” drug delivery agents has attracted particular interest in this area. This review will discuss efforts in our research group to study the salmycin class of “Trojan Horse” antibiotics. Inspired by the natural design of the salmycins, a series of desferridanoxamine-antibiotic conjugates were synthesized and tested in microbial growth inhibition assays. The results of these studies will be related to understanding the role of drug release in siderophore-mediated drug delivery with implications for future siderophore-drug conjugate design.

Keywords

Siderophores Salmycins Danoxamine Antibiotics Resistance “Trojan Horse” Iron transport Drug delivery 

Notes

Acknowledgments

We gratefully acknowledge the National Institutes of Health (NIH) research grants RO1 AI054193, NIH AI 030988, and NIH GM025845 for financial support. We thank Irmgard Heinemann and Uta Wohlfeld for their excellent technical assistance with growth promotion and growth inhibition assays at the HKI. MJM gratefully acknowledges the kind hospitality of the HKI and the University of Notre Dame for a sabbatical opportunity in Jena, Germany. TAW gratefully acknowledges the University of Notre Dame Chemistry-Biochemistry-Biology (CBBI) Interface Program and NIH training grant T32GM075762 for a fellowship and the kind hospitality of the HKI for a research internship opportunity.

References

  1. Ash C (1996) Antibiotic resistance: the new apocalypse? Trends Microbiol 4:371–372. doi: 10.1016/0966-842X(96)30028-0 PubMedCrossRefGoogle Scholar
  2. Benz G, Schröder T, Kurz J, Wünsche C, Karl W, Steffen GJ, Pfitzner J, Schmidt D (1982) Konstitution der deferriform der albomycine δ1, δ2 und ε. Angew Chem Int Ed 94:552–553Google Scholar
  3. Bergeron RJ, Pegram JJ (1988) An efficient total synthesis of desferrioxamine B. J Org Chem 53:3131–3134. doi: 10.1021/jo00249a001 CrossRefGoogle Scholar
  4. Bickel H, Gäumann E, Nussberg G, Reusser P, Vischer E, Voser W, Wettstein A, Zähner H (1960) Stoffwechselprodukte von Actinomyceten. 25 Mitteilung: über die isolierung und charakterisierung der ferrimycine A1 und A2, neuer antibiotika der sideromycin-gruppe. Helv Chim Acta 43:2105–2118. doi: 10.1002/hlca.19600430730 CrossRefGoogle Scholar
  5. Bickel H, Mertens P, Prelog V, Seibl J, Walser A (1965) Constitution of ferrimycin A1. Antimicrob Agents Chemother 5:951–957PubMedGoogle Scholar
  6. Braun V (1999) Active transport of siderophore-mimicking antibacterials across the outer membrane. Drug Resist Updat 2:363–369. doi: 10.1054/drup.1999.0107 PubMedCrossRefGoogle Scholar
  7. Braun V, Günthner H, Hantke K, Zimmerman L (1983) Intracellular activation of albomycin in Escherichia coli and Salmonella typhimurium. J Bacteriol 156:308–315PubMedGoogle Scholar
  8. Braun V, Pramanik A, Gwinner T (2008) Use of sideromycins as tools and antibiotics. Paper presented at the 6th international biometals symposium, Santiago de Compostela, Spain, 14–18 July 2008Google 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-β-lactam conjugates that use specific iron uptake pathways for entry into bacteria. Antimicrob Agents Chemother 36:2166–2175PubMedGoogle Scholar
  10. Budzikiewicz H (2001) Siderophore-antibiotic conjugates used as trojan horses against Pseudomonas aeruginosa. Curr Top Med Chem 1:73–82. doi: 10.2174/1568026013395524 PubMedCrossRefGoogle Scholar
  11. Challis GL, Hopwood DA (2003) Synergy and contingency as driving forces for the evolution of multiple secondary metabolite production by Streptomyces species. Proc Natl Acad Sci USA 100:14555–14561. doi: 10.1073/pnas.1934677100 PubMedCrossRefGoogle Scholar
  12. Clarke TE, Braun V, Winkelmann G, Tari LW, Vogel HJ (2002) X-ray crystallographic structures of the Eschericia coli periplasmic protein FhuD bound to hydroxamate-type siderophores and the antibiotic albomycin. J Biol Chem 277:13966–13972. doi: 10.1074/jbc.M109385200 PubMedCrossRefGoogle Scholar
  13. Codd R (2008) Traversing the coordination chemistry and chemical biology of hydroxamic acids. Coord Chem Rev 252:1387–1408. doi: 10.1016/j.ccr.2007.08.001 CrossRefGoogle Scholar
  14. Dong L, Roosenberg JM, Miller MJ (2002) Total synthesis of deferrisalmycin B. J Am Chem Soc 124:15001–15005. doi: 10.1021/ja028386w PubMedCrossRefGoogle Scholar
  15. Ferguson AD, Braun V, Fiedler HP, Coulton JW, Diederichs K, Welte W (2000) Crystal structure of the antibiotic albomycin in complex with the outer membrane transporter FhuA. Protein Sci 9:956–963PubMedCrossRefGoogle Scholar
  16. 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
  17. Gause GF (1955) Recent studies on albomycin, a new antibiotic. BMJ 12:1177–1179CrossRefGoogle Scholar
  18. Guerinot ML (1994) Microbial iron transport. Annu Rev Microbiol 48:743–772. doi: 10.1146/annurev.mi.48.100194.003523 PubMedCrossRefGoogle Scholar
  19. Hartmann A, Fiedler HP, Braun V (1979) Uptake and conversion of the antibiotic albomycin by Eschericia coli K-12. Eur J Biochem 99:517–524. doi: 10.1111/j.1432-1033.1979.tb13283.x PubMedCrossRefGoogle Scholar
  20. Grand Challenges in Global Health (2008) Create drugs and delivery systems to limit drug resistance. http://www.gcgh.org/LimitDrugResistance/Topics/DoNotGenerateResistance/Pages/default.aspx. Cited 11 Nov 2008
  21. Heinisch L, Wittmann S, Stoiber T, Berg A, Ankel-Fuchs D, Möllmann U (2002) Highly antibacterial active amnioacyl penicillin conjugates with bis-catecholate siderophores based on secondary diamino acids and related compounds. J Med Chem 45:3032–3040. doi: 10.1021/jm010546b PubMedCrossRefGoogle Scholar
  22. Heinisch L, Wittmann S, Stoiber T, Scherlitz-Hoffmann I, Ankel-Fuchs D, Möllmann U (2003) New tris- and tetrakis-catecholate siderophores based on polyazaalkanoic acids and their β-lactam conjugates. Arzneim-Forschung Drug Res 53:188–195Google Scholar
  23. Hennard C, Truong QC, Desnottes JF, Paris JM, Moreau NJ, Abdallah MA (2001) Synthesis and activities of pyoverdin–quinolone adducts: a prospective approach to a specific therapy against Pseudomonas aeruginosa. J Med Chem 44:2139–2151. doi: 10.1021/jm990508g PubMedCrossRefGoogle Scholar
  24. Ho WH, Wong HNC (1995) Chiral liquid crystalline compounds from d-(+)-glucose. Tetrahedron 51:7373–7388. doi: 10.1016/0040-4020(95)00386-M CrossRefGoogle Scholar
  25. Huber P, Leuenberger H, Keller-Schierlein W (1986) Danoxamin, der eisenbindende teil des sideromycin-antibioticums danomycin. Helv Chim Acta 69:236–245. doi: 10.1002/hlca.19860690128 CrossRefGoogle Scholar
  26. Jarvis LM (2008) An uphill battle. C E News 86:15–20Google Scholar
  27. Klare I, Heier H, Claus H, Reissbrodt R, Witte W (1995) VanA-mediated high-level glycopeptides resistance in Enterococcus faecium from animal husbandry. FEMS Microbiol Lett 125:165–172. doi: 10.1111/j.1574-6968.1995.tb07353.x PubMedCrossRefGoogle Scholar
  28. Krewulak KD, Vogel HJ (2008) Structural biology of bacterial iron uptake. Biochim Biophys Acta 1778:1781–1804. doi: 10.1016/j.bbamem.2007.07.026 PubMedCrossRefGoogle Scholar
  29. Marshall E (2008) The bacteria fight back. Science 321:356–364. doi: 10.1126/science.321.5887.356 CrossRefGoogle Scholar
  30. Miethke M, Marahiel MA (2007) Siderophore-based iron acquisition and pathogen control. Microbiol Mol Biol Rev 71:413–451. doi: 10.1128/MMBR.00012-07 PubMedCrossRefGoogle Scholar
  31. Miller MJ, Malouin F (1993) Microbial iron chelators as drug delivery agents: the rational design and synthesis of siderophore-drug conjugates. Acc Chem Res 26:241–249. doi: 10.1021/ar00029a003 CrossRefGoogle Scholar
  32. 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, Dolence EK, 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 22:61–75PubMedCrossRefGoogle Scholar
  33. Mitscher LA (2008) Coevolution: mankind and microbes. J Nat Prod 71:497–509. doi: 10.1021/np078017j PubMedCrossRefGoogle Scholar
  34. Möllmann U, Dong L, Vertesy L, Miller MJ (2004) Salmycins—natural siderophore-drug conjugates: Prospects for modification and investigation based on successful total synthesis. Paper presented at the 2nd international Biometals symposium, Garmisch-Partenkirchen, Germany, 3–5 Sept 2004Google Scholar
  35. Möllmann U, Heinisch L, Bauernfeind A, Thilo K, Ankel-Fuchs D (2009) Siderophores as drug delivery agents: application of the “Trojan Horse” strategy. Biometals. doi: 10.1007/s10534-009-9219-2 Google Scholar
  36. Nathan C (2004) Antibiotics at the crossroads. Nature 431:899–902. doi: 10.1038/431899a PubMedCrossRefGoogle Scholar
  37. Neilands JB (1995) Siderophores: structure and function of microbial iron transport compounds. J Biol Chem 270:26723–26726PubMedGoogle Scholar
  38. Neres J, Labello NP, Somu RV, Boshoff HI, Wilson DJ, Vannada J, Chen L, Barry CE, Bennet EM, Aldich 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 51:5349–5370. doi: 10.1021/jm800567v PubMedCrossRefGoogle Scholar
  39. Nikaido H, Nikaido K, Harayama S (1991) Identification and characterization of porins in Pseudomonas aeruginosa. J Biol Chem 266:770–779PubMedGoogle Scholar
  40. Nolan EM, Walsh CT (2008) Investigations of the MceIJ-catalyzed posttranslational modification of the microcin E492 C-terminus: linkage of ribosomal and nonribosomal peptides to form “Trojan Horse” antibiotics. Biochemistry 47:9289–9299. doi: 10.1021/bi800826j PubMedCrossRefGoogle Scholar
  41. Ogawa T, Kaburagi T (1982) Synthesis of a branched d-glucotetraose, the repeating unit of the extracellular polysaccharides of Grifola umbellate, Sclerotinia libertiana, Porodisculus pendulus, and Schizophyllum commune fries. Carbohydr Res 103:53–64. doi: 10.1016/S0008-6215(82)80007-4 CrossRefGoogle Scholar
  42. Pramanik A, Braun V (2006) Albomycin uptake via a ferric hydroxamate transport system of Streptococcus pneumoniae R6. J Bacteriol 188:3878–3886. doi: 10.1128/JB.00205-06 PubMedCrossRefGoogle Scholar
  43. 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 297:459–469. doi: 10.1016/j.ijmm.2007.03.002 PubMedCrossRefGoogle Scholar
  44. Quadri LEN (2007) Strategic paradigm shifts in the antimicrobial drug discovery process of the 21st century. Infect Disord Drug Targets 7:230–237. doi: 10.2174/187152607782110040 PubMedCrossRefGoogle Scholar
  45. Ratledge CL, Dover G (2000) Iron metabolism in pathogenic bacteria. Annu Rev Microbiol 54:881–941. doi: 10.1146/annurev.micro.54.1.881 PubMedCrossRefGoogle Scholar
  46. Richmond MH, Clark DC, Wotton S (1976) Indirect method for assessing the penetration of beta-lactamase-nonsusceptible penicillins and cephalosporins in Eschericia coli. Antimicrob Agents Chemother 10:215–218PubMedGoogle Scholar
  47. Rivault F, Liébert C, Burger A, Hoegy F, Abdallah MA, Schalk IJ, Mislin GLA (2007) Synthesis of pyochelin–norfloxacin conjugates. Bioorg Med Chem Lett 17:640–644. doi: 10.1016/j.bmcl.2006.11.005 PubMedCrossRefGoogle Scholar
  48. Rook G (2008) Anti-mycobacterial mycobactin-linked glyconanoparticles. In: Grants awarded. Grand Challenges in Global Health. http://www.gcgh.org/explorations/Pages/GrantsAwarded.aspx. Cited 11 Nov 2008
  49. Roosenberg JM, Miller MJ (2000) Total synthesis of the siderophore danoxamine. J Org Chem 65:4833–4838. doi: 10.1021/jo000050m PubMedCrossRefGoogle Scholar
  50. Roosenberg JM, Lin Y-M, Lu Y, Miller MJ (2000) Studies and syntheses of siderophores, microbial iron chelators, and analogs as potential drug delivery agents. Curr Med Chem 7:159–197PubMedGoogle Scholar
  51. Sackmann W, Preusser P, Neipp L, Kradolfer F, Gross F (1962) Ferrimycin A, a new iron containing antibiotic. Antibiot Chemother 12:34–45PubMedGoogle Scholar
  52. Schumann G, Möllmann U (2001) A screening system for xenosiderophores as potential drug delivery agents in mycobacteria. Antimicrob Agents Chemother 45:1317–1322. doi: 10.1128/AAC.45.5.1317-1322.2001 PubMedCrossRefGoogle Scholar
  53. Snapper SB, Melton RE, Mustafa S, Kieser T, Jacobs WR (1990) Isolation and characterization of efficient plasmid transformation mutants of Mycobacterium smegmatis. Mol Microbiol 4:1911–1919. doi: 10.1111/j.1365-2958.1990.tb02040.x PubMedCrossRefGoogle Scholar
  54. 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 279:28233–28242. doi: 10.1074/jbc.M400228200 PubMedCrossRefGoogle Scholar
  55. Vértesy L, Aretz W, Fehlhaber H-W, Koger H (1995) Salmycin A–D, Antibiotika aus Streptomycese violaceus, DSM 8286, mit siderophore-aminoglycosid-struktur. Helv Chim Acta 78:46–60. doi: 10.1002/hlca.19950780105 CrossRefGoogle Scholar
  56. Wach JY, Bonazzi S, Gademann K (2008) Antimicrobial surfaces through natural product hybrids. Angew Chem Int Ed 47:7123–7126. doi: 10.1002/anie.200801570 CrossRefGoogle Scholar
  57. Walsh C (2003) Antibiotics: actions, origins, resistance. ASM Press, Washington, DCGoogle Scholar
  58. Winkelmann G, van der Helm D, Neilands JB (1987) Iron transport in microbes, plants, and animals. VCH Press, Weinheim, pp 1–533Google Scholar
  59. Witte W, Cuny C, Braulke C, Heuck D (1994) Clonal dissemination of two MRSA strains in Germany. Epidemiol Infect 113:67–73PubMedCrossRefGoogle Scholar
  60. Wittmann S, Schnabelrauch M, Scherlitz-Hoffmann I, Möllmann U, Ankel-Fuchs D, Heinisch L (2002) New synthetic siderophores and their β-lactam conjugates based on amino acids and dipeptides. Bioorg Med Chem 10:1659–1670. doi: 10.1016/S0968-0896(02)00044-5 PubMedCrossRefGoogle Scholar
  61. Zähner H, Diddens H, Keller-Schierlein W, Nägeli HU (1977) Some experiments with semisynthetic sideromycins. Jpn J Antibiot 30:S201–S206Google Scholar
  62. Zimmermann W (1980) Penetration of β-lactam antibiotics into their target enzymes in Pseudomonas aeruginosa: comparison of a highly sensitive mutant with its parent strain. Antimicrob Agents Chemother 18:94–100PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Timothy A. Wencewicz
    • 1
  • Ute Möllmann
    • 2
  • Timothy E. Long
    • 1
  • Marvin J. Miller
    • 1
    Email author
  1. 1.Department of Chemistry and BiochemistryUniversity of Notre DameNotre DameUSA
  2. 2.Department of Molecular and Applied MicrobiologyLeibniz Insitute for Natural Product Research and Infection Biology—Hans-Knoell InstituteJenaGermany

Personalised recommendations