Details
| Translated title of the contribution | Zielgerichtete bakterielle Lokalisation und infektionsinduzierte Freisetzung von antibiotischen Colistin-Konjugaten |
|---|---|
| Original language | English |
| Pages (from-to) | 17989-17997 |
| Number of pages | 9 |
| Journal | Angewandte Chemie - International Edition |
| Volume | 60 |
| Issue number | 33 |
| Early online date | 7 Jul 2021 |
| Publication status | Published - 3 Aug 2021 |
Abstract
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.
Keywords
- Antibiotics, drug conjugates, drug delivery, immune activation, natural products
ASJC Scopus subject areas
- Chemical Engineering(all)
- Catalysis
- Chemistry(all)
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In: Angewandte Chemie - International Edition, Vol. 60, No. 33, 03.08.2021, p. 17989-17997.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Selective Bacterial Targeting and Infection-Triggered Release of Antibiotic Colistin Conjugates
AU - Tegge, Werner
AU - Guerra, Giulia
AU - Höltke, Alexander
AU - Schiller, Lauritz
AU - Beutling, Ulrike
AU - Harmrolfs, Kirsten
AU - Gröbe, Lothar
AU - Wullenkord, Hannah
AU - Xu, Chunfa
AU - Weich, Herbert
AU - Brönstrup, Mark
N1 - Funding Information: We thank Brigitte Kornak (HZI) for support with peptide synthesis and purification and Prof. Dr. Henk Garritsen from the Institute of Clinical Transfusion Medicine of the Klinikum Braunschweig, Germany, for providing us with plateletpheresis filters. This work was co‐funded by the German Centre for infection research (Grant no TTU09.710), the President's Initiative and Network Fund of the Helmholtz Association of German Research Centres (HGF) under contract number VH‐GS‐202, and the Helmholtz Shandong International Lab. GG received funding from Università Politecnica delle Marche, Ancona. Open access funding enabled and organized by Projekt DEAL.
PY - 2021/8/3
Y1 - 2021/8/3
N2 - 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.
AB - 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.
KW - Antibiotics
KW - drug conjugates
KW - drug delivery
KW - immune activation
KW - natural products
UR - http://www.scopus.com/inward/record.url?scp=85109193520&partnerID=8YFLogxK
U2 - 10.1002/anie.202104921
DO - 10.1002/anie.202104921
M3 - Article
AN - SCOPUS:85109193520
VL - 60
SP - 17989
EP - 17997
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
SN - 1433-7851
IS - 33
ER -