, Volume 28, Issue 3, pp 541–551 | Cite as

Siderophore–fluoroquinolone conjugates containing potential reduction-triggered linkers for drug release: synthesis and antibacterial activity

  • Cheng Ji
  • Marvin J. Miller


Syntheses of two Siderophore–fluoroquinolone conjugates with a potential reduction triggered linker for drug release are described. The “trimethyl lock” based linker incorporated in the conjugates was designed to be activated by taking advantage of the reductive pathway of bacterial iron metabolism. Electrochemical and LC–MS studies indicated that the linker is thermodynamically reducible by common biological reductants and the expected lactonization proceeds rapidly with concomitant release of the drug. Antibacterial activity assays revealed that conjugates with the reduction-triggered linker were more potent than their counterparts with a stable linker, which suggests that drug release occurs inside bacterial cells.


Siderophores Antibiotics Trojan horse Iron transport Drug delivery Drug release 



Partial funding for this work was provided by NIH Grant AI054193. C. J. gratefully acknowledges the UND Chemistry-Biochemistry-Biology (CBBI) Interface Program funded by NIH (T32GM075762) for fellowship support. We gratefully acknowledge the use of the NMR facilities provided by the Lizzadro Magnetic Resonance Research Center at the University of Notre Dame (UND) under the direction of Dr. Jaroslav Zajicek and the mass spectrometry services provided by The UND Mass Spectrometry & Proteomics Facility (Mrs. N. Sevova, Dr. W. Boggess, and Dr. M. V. Joyce; supported by the National Science Foundation under CHE-0741793). We gratefully thank Mrs. Patricia A. Miller (UND) for antibacterial susceptibility testing.

Supplementary material

10534_2015_9830_MOESM1_ESM.doc (3.7 mb)
Experimental procedures, copies of spectral data, and characterization data. This material is available free of charge via the internet (DOC 3814 kb)


  1. Boucher HW et al (2009) Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 48:1–12. doi: 10.1086/595011 CrossRefPubMedGoogle Scholar
  2. Braun V, Günthner K, Hantke K, Zimmermann L (1983) Intracellular activation of albomycin in Escherichia coli and Salmonella typhimurium. J Bacteriol 156:308–315PubMedCentralPubMedGoogle Scholar
  3. Braun V, Pramanik A, Gwinner T, Koberle M, Bohn E (2009) Sideromycins: tools and antibiotics. Biometals 22:3–13. doi: 10.1007/s10534-008-9199-7 CrossRefPubMedCentralPubMedGoogle Scholar
  4. Diarra MS et al (1996) Species selectivity of new siderophore-drug conjugates that use specific iron uptake for entry into bacteria. Antimicrob Agents Chemother 40:2610–2617PubMedCentralPubMedGoogle Scholar
  5. Fernandez L, Hancock REW (2012) Adaptive and mutational resistance: role of porins and efflux pumps in drug resistance. Clin Microbiol Rev 25:661–681. doi: 10.1128/cmr.00043-12 CrossRefPubMedCentralPubMedGoogle Scholar
  6. 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 CrossRefPubMedGoogle Scholar
  7. Harrington JM, Crumbliss AL (2009) The redox hypothesis in siderophore-mediated iron uptake. Biometals 22:679–689. doi: 10.1007/s10534-009-9233-4 CrossRefPubMedGoogle Scholar
  8. 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 CrossRefPubMedGoogle Scholar
  9. Ji C, Miller MJ (2012) Chemical syntheses and in vitro antibacterial activity of two desferrioxamine B-ciprofloxacin conjugates with potential esterase and phosphatase triggered drug release linkers. Bioorg Med Chem 20:3828–3836. doi: 10.1016/j.bmc.2012.04.034 CrossRefPubMedCentralPubMedGoogle Scholar
  10. Ji C, Juárez-Hernández RE, Miller MJ (2012a) Exploiting bacterial iron acquisition: siderophore conjugates. Future Med Chem 4:297–313. doi: 10.4155/fmc.11.191 CrossRefPubMedGoogle Scholar
  11. Ji C, Miller PA, Miller MJ (2012b) Iron transport-mediated drug delivery: practical syntheses and in vitro antibacterial studies of tris-catecholate siderophore-aminopenicillin conjugates reveals selectively potent antipseudomonal activity. J Am Chem Soc 134:9898–9901. doi: 10.1021/ja303446w CrossRefPubMedCentralPubMedGoogle Scholar
  12. Levine MN, Raines RT (2012) Trimethyl lock: a trigger for molecular release in chemistry, biology, and pharmacology. Chem Sci 3:2412–2420. doi: 10.1039/c2sc20536j CrossRefPubMedCentralPubMedGoogle Scholar
  13. Levy SB, Marshall B (2004) Antibacterial resistance worldwide: causes, challenges and responses. Nat Med 10:S122–S129. doi: 10.1038/nm1145 CrossRefPubMedGoogle Scholar
  14. Mendoza MF, Hollabaugh NM, Hettiarachchi SU, McCarley RL (2012) Human NAD(P)H:quinone oxidoreductase Type I (hNQO1) activation of quinone propionic acid trigger groups. Biochemistry 51:8014–8026. doi: 10.1021/bi300760u CrossRefPubMedCentralPubMedGoogle Scholar
  15. 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 CrossRefPubMedCentralPubMedGoogle Scholar
  16. Mislin GLA, Schalk IJ (2014) Siderophore-dependent iron uptake systems as gates for antibiotic Trojan horse strategies against Pseudomonas aeruginosa. Metallomics 6:408–420. doi: 10.1039/c3mt00359k CrossRefPubMedGoogle Scholar
  17. Mitscher LA (2005) Bacterial topoisomerase inhibitors: quinolone and pyridone antibacterial agents. Chem Rev 105:559–592. doi: 10.1021/cr030101q CrossRefPubMedGoogle Scholar
  18. Möllmann U, Heinisch L, Bauernfeind A, Köhler T, Ankel-Fuchs D (2009) Siderophores as drug delivery agents: application of the “Trojan Horse” strategy. Biometals 22:615–624. doi: 10.1007/s10534-009-9219-2 CrossRefPubMedGoogle Scholar
  19. Müller G, Raymond KN (1984) Specificity and mechanism of ferrioxamine-mediated iron transport in Streptomyces pilosus. J Bacteriol 160:304–312PubMedCentralPubMedGoogle Scholar
  20. Noël S, Gasser V, Pesset B, Hoegy F, Rognan D, Schalk IJ, Mislin GLA (2011) Synthesis and biological properties of conjugates between fluoroquinolones and a N3″-functionalized pyochelin. Org Biomol Chem 9:8288–8300. doi: 10.1039/c1ob06250f CrossRefPubMedGoogle Scholar
  21. Ong W, Yang Y, Cruciano AC, McCarley RL (2008) Redox-triggered contents release from liposomes. J Am Chem Soc 130:14739–14744. doi: 10.1021/ja8050469 CrossRefPubMedCentralPubMedGoogle Scholar
  22. Page MGP (2013) Siderophore conjugates. Ann NY Acad Sci 1277:115–126. doi: 10.1111/nyas.12024 CrossRefPubMedGoogle Scholar
  23. Pages JM, James CE, Winterhalter M (2008) The porin and the permeating antibiotic: a selective diffusion barrier in Gram-negative bacteria. Nat Rev Microbiol 6:893–903. doi: 10.1038/nrmicro1994 CrossRefPubMedGoogle Scholar
  24. Projan SJ (2003) Why is big pharma getting out of antibacterial drug discovery? Curr Opin Microbiol 6:427–430. doi: 10.1016/j.mib.2003.08.003 CrossRefPubMedGoogle Scholar
  25. Rivault F, Liebert 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 CrossRefPubMedGoogle Scholar
  26. Roosenberg JM, Miller MJ (2000) Total synthesis of the siderophore danoxamine. J Org Chem 65:4833–4838. doi: 10.1021/jo000050m CrossRefPubMedGoogle Scholar
  27. Schröder 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 CrossRefPubMedGoogle Scholar
  28. Spellberg B et al (2008) The epidemic of antibiotic-resistant infections: a call to action for the medical community from the Infectious Diseases Society of America. Clin Infect Dis 46:155–164. doi: 10.1086/524891 CrossRefPubMedGoogle Scholar
  29. Vértesy L, Aretz W, Fehlhaber HW, Kogler H (1995) Salmycin A-D, antibiotics from Streptomyces violaceus, DSM 8286, having a siderophore aminoglycoside structure. Helv Chim Acta 78:46–60. doi: 10.1002/hlca.19950780105 CrossRefGoogle Scholar
  30. Wencewicz TA, Miller MJ (2013) Biscatecholate-monohydroxamate mixed ligand siderophore-carbacephalosporin conjugates are selective sideromycin antibiotics that target Acinetobacter baumannii. J Med Chem 56:4044–4052. doi: 10.1021/jm400265k CrossRefPubMedCentralPubMedGoogle Scholar
  31. Wencewicz TA, Möllmann U, Long TE, Miller MJ (2009) 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. Biometals 22:633–648. doi: 10.1007/s10534-009-9218-3 CrossRefPubMedCentralPubMedGoogle Scholar
  32. Wencewicz TA, Long TE, Möllmann U, Miller MJ (2013) Trihydroxamate siderophore–fluoroquinolone conjugates are selective sideromycin antibiotics that target Staphylococcus aureus. Bioconjug Chem 24:473–486. doi: 10.1021/bc300610f CrossRefPubMedCentralPubMedGoogle Scholar
  33. Zheng T, Nolan EM (2014) Enterobactin-mediated delivery of β-lactam antibiotics enhances antibacterial activity against pathogenic Escherichia coli. J Am Chem Soc 136:9677–9691. doi: 10.1021/ja503911p CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Chemistry and BiochemistryUniversity of Notre DameNotre DameUSA

Personalised recommendations