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

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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.

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Abbreviations

DHBS:

2,3-Dihydroxybenzoyl serine

DTT:

1,4-Dithiothreitol

Ent:

Enterobactin

GSH:

Glutathione

GSSG:

Glutathione disulfide

TCEP:

Tris(2-carboxyethyl)phosphine

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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).

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  1. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

    Wilma Neumann & Elizabeth M. Nolan

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  1. Wilma Neumann
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  2. Elizabeth M. Nolan
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Correspondence to Elizabeth M. Nolan.

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Neumann, W., Nolan, E.M. Evaluation of a reducible disulfide linker for siderophore-mediated delivery of antibiotics. J Biol Inorg Chem 23, 1025–1036 (2018). https://doi.org/10.1007/s00775-018-1588-y

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