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BioMetals

, Volume 22, Issue 4, pp 615–624 | Cite as

Siderophores as drug delivery agents: application of the “Trojan Horse” strategy

  • Ute MöllmannEmail author
  • Lothar Heinisch
  • Adolf Bauernfeind
  • Thilo Köhler
  • Dorothe Ankel-Fuchs
Article

Abstract

The outer membrane permeability barrier is an important resistance factor of bacterial pathogens. In combination with drug inactivating enzymes, target alteration and efflux, it can increase resistance dramatically. A strategy to overcome this membrane-mediated resistance is the misuse of bacterial transport systems. Most promising are those for iron transport. They are vital for virulence and survival of bacteria in the infected host, where iron depletion is a defense mechanism against invading pathogens. We synthesized biomimetic siderophores as shuttle vectors for active transport of antibiotics through the bacterial membrane. Structure activity relationship studies resulted in siderophore aminopenicillin conjugates that were highly active against Gram-negative pathogens which play a crucial role in destructive lung infections in cystic fibrosis patients and in severe nosocomial infections. The mechanism of action and the uptake of the compounds via specific iron siderophore transport routes were demonstrated. The novel conjugates were active against systemic Pseudomonas aeruginosa infections in mice with ED50 values comparable to the quinolone ofloxacin and show low toxicity.

Keywords

Siderophores Aminopenicillin conjugates Permeability barrier Efflux Pseudomonas aeruginosa 

Notes

Acknowledgments

We thank Klaus Hantke, University of Tübingen, Germany, for the generous support with the porin mutants as well as with the iron transport mutants, Franz-Josef Schmitz, University of Düsseldorf, Germany, for testing in vitro activity against clinical P. aeruginosa isolates, Monika Golembiewski and Irmgard Heinemann for their excellent technical assistance. Financial support by German Ministry of Education and Research, BMBF grant #0311232 is gratefully acknowledged.

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Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Ute Möllmann
    • 1
    Email author
  • Lothar Heinisch
    • 1
  • Adolf Bauernfeind
    • 2
  • Thilo Köhler
    • 3
  • Dorothe Ankel-Fuchs
    • 4
  1. 1.Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell InstituteJenaGermany
  2. 2.Micoer InstituteMunichGermany
  3. 3.Department of Microbiology and Molecular MedicineCentre Médical UniversitaireGenevaSwitzerland
  4. 4.Gruenenthal GmbHAachenGermany

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