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JBIC Journal of Biological Inorganic Chemistry

, Volume 23, Issue 7, pp 1025–1036 | Cite as

Evaluation of a reducible disulfide linker for siderophore-mediated delivery of antibiotics

  • Wilma Neumann
  • Elizabeth M. NolanEmail author
Original Paper
Part of the following topical collections:
  1. Alison Butler: Papers in Celebration of Her 2018 ACS Alfred Bader Award in Bioorganic or Bioinorganic Chemistry

Abstract

Bacterial iron uptake machinery can be hijacked for the targeted delivery of antibiotics into pathogens by attaching antibiotics to siderophores, iron chelators that are employed by bacteria to obtain this essential nutrient. We synthesized and evaluated Ent–SS–Cipro, a siderophore–antibiotic conjugate comprised of the triscatecholate siderophore enterobactin and the fluoroquinolone antibiotic ciprofloxacin that contains a self-immolative disulfide linker. This linker is designed to be cleaved after uptake into the reducing environment of the bacterial cytoplasm. We show that the disulfide bond of Ent–SS–Cipro is cleaved by reducing agents, including the cellular reductant glutathione, which results in release of the unmodified fluoroquinolone antibiotic. Antibacterial activity assays against a panel of Escherichia coli show that Ent–SS–Cipro exhibits activity against some, but not all, E. coli. This work informs the design of siderophore–antibiotic conjugates, particularly those carrying antibiotics with cytoplasmic targets that require release after uptake into bacterial cells, and indicates that disulfide linkers may not be generally applicable for conjugation strategies of antibiotics.

Graphical abstract

Keywords

Siderophore Antibiotic conjugate Disulfide linker Targeted delivery Iron uptake 

Abbreviations

DHBS

2,3-Dihydroxybenzoyl serine

DTT

1,4-Dithiothreitol

Ent

Enterobactin

GSH

Glutathione

GSSG

Glutathione disulfide

TCEP

Tris(2-carboxyethyl)phosphine

Notes

Acknowledgements

We thank the National Institutes of Health (NIH Grants 1R21AI126465 and 1R01AI114625) for financial support; Lynette Cegelski for providing E. coli UTI89; Manuela Raffatellu for providing E. coli JB2; Ardeypharm GmbH for providing E. coli Nissle 1917. W.N. acknowledges the German National Academy of Sciences Leopoldina for a postdoctoral fellowship (LPDS 2015-08). MS instrumentation maintained by the MIT Center for Environmental Health Sciences (CEHS) is supported by a core center grant from the National Institute of Environmental Health Sciences, National Institutes of Health (NIEHS grant P30-ES002109).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

775_2018_1588_MOESM1_ESM.pdf (4.1 mb)
Supplementary material 1 (PDF 4185 kb)

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Copyright information

© SBIC 2018

Authors and Affiliations

  1. 1.Department of ChemistryMassachusetts Institute of TechnologyCambridgeUSA

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