Selective Bacterial Targeting and Infection-Triggered Release of Antibiotic Colistin Conjugates.
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Authors
Tegge, WernerGuerra, Giulia
Höltke, Alexander
Schiller, Lauritz
Beutling, Ulrike
Harmrolfs, Kirsten
Gröbe, Lothar
Wullenkord, Hannah
Xu, Chunfa
Weich, Herbert
Brönstrup, Mark

Issue Date
2021-07-05
Metadata
Show full item recordAbstract
In order to render potent, but toxic antibiotics more selective, we have explored a novel conjugation strategy that includes drug accumulation followed by infection-triggered release of the drug. Bacterial targeting was achieved using a modified fragment of the human antimicrobial peptide ubiquicidin, as demonstrated by fluorophore-tagged variants. To limit the release of the effector colistin only to infection-related situations, we introduced a linker that was cleaved by neutrophil elastase (NE), an enzyme secreted by neutrophil granulocytes at infection sites. The linker carried an optimized sequence of amino acids that was required to assure sufficient cleavage efficiency. The antibacterial activity of five regioisomeric conjugates prepared by total synthesis was masked, but was released upon exposure to recombinant NE when the linker was attached to amino acids at the 1- or the 3-position of colistin. A proof-of-concept was achieved in co-cultures of primary human neutrophils and Escherichia coli that induced the secretion of NE, the release of free colistin, and an antibacterial efficacy that was equal to that of free colistin.Citation
Angew Chem Int Ed Engl. 2021 Aug 9;60(33):17989-17997. doi: 10.1002/anie.202104921. Epub 2021 Jul 5.Affiliation
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.Publisher
Wiley-VCHPubMed ID
34097810Type
ArticleLanguage
enEISSN
1521-3773ae974a485f413a2113503eed53cd6c53
10.1002/anie.202104921
Scopus Count
The following license files are associated with this item:
- Creative Commons
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