Details
| Originalsprache | Englisch |
|---|---|
| Aufsatznummer | e202408360 |
| Seitenumfang | 8 |
| Fachzeitschrift | Angewandte Chemie - International Edition |
| Jahrgang | 63 |
| Ausgabenummer | 47 |
| Frühes Online-Datum | 8 Aug. 2024 |
| Publikationsstatus | Veröffentlicht - 11 Nov. 2024 |
Abstract
The use of highly potent but very toxic antibiotics such as colistin has become inevitable due to the rise of antimicrobial resistance. We aimed for a chemically-triggered, controlled release of colistin at the infection site to lower its systemic toxicity by harnessing the power of click-to-release reactions. Kinetic experiments with nine tetrazines and three dienophiles demonstrated a fast release via an inverse-electron-demand Diels–Alder reaction between trans-cyclooctene (TCO) and the amine-functionalised tetrazine Tz7. The antibiotic activity of colistin against Escherichia coli was masked by TCO units, but restored upon reaction with d-Ubi−Tz, a tetrazine functionalised with the bacterial binding peptide d-Ubi29–41. While standard TCO did not improve toxicity against human proximal tubular kidney HK-2 cells, the installation of an aspartic acid-modified TCO masking group reduced the overall charge of the peptide and entry to the kidney cells, thereby dramatically lowering its toxicity. The analog Col−(TCO-Asp)1 had favourable pharmacokinetic properties in mice and was successfully activated locally in the lung by d-Ubi−Tz in an in vivo infection model, whereas it remained inactive and non-harmful without the chemical trigger. This study constitutes the first example of a systemically acting two-component antibiotic with improved drug tolerability.
ASJC Scopus Sachgebiete
- Chemische Verfahrenstechnik (insg.)
- Katalyse
- Chemie (insg.)
- Allgemeine Chemie
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in: Angewandte Chemie - International Edition, Jahrgang 63, Nr. 47, e202408360, 11.11.2024.
Publikation: Beitrag in Fachzeitschrift › Artikel › Forschung › Peer-Review
}
TY - JOUR
T1 - A Targeted Click-to-Release Activation of the Last-Resort Antibiotic Colistin Reduces its Renal Cell Toxicity
AU - Charoenpattarapreeda, Jiraborrirak
AU - Tegge, Werner
AU - Xu, Chunfa
AU - Harmrolfs, Kirsten
AU - Hinkelmann, Bettina
AU - Wullenkord, Hannah
AU - Hotop, Sven Kevin
AU - Beutling, Ulrike
AU - Rox, Katharina
AU - Brönstrup, Mark
N1 - Publisher Copyright: © 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.
PY - 2024/11/11
Y1 - 2024/11/11
N2 - The use of highly potent but very toxic antibiotics such as colistin has become inevitable due to the rise of antimicrobial resistance. We aimed for a chemically-triggered, controlled release of colistin at the infection site to lower its systemic toxicity by harnessing the power of click-to-release reactions. Kinetic experiments with nine tetrazines and three dienophiles demonstrated a fast release via an inverse-electron-demand Diels–Alder reaction between trans-cyclooctene (TCO) and the amine-functionalised tetrazine Tz7. The antibiotic activity of colistin against Escherichia coli was masked by TCO units, but restored upon reaction with d-Ubi−Tz, a tetrazine functionalised with the bacterial binding peptide d-Ubi29–41. While standard TCO did not improve toxicity against human proximal tubular kidney HK-2 cells, the installation of an aspartic acid-modified TCO masking group reduced the overall charge of the peptide and entry to the kidney cells, thereby dramatically lowering its toxicity. The analog Col−(TCO-Asp)1 had favourable pharmacokinetic properties in mice and was successfully activated locally in the lung by d-Ubi−Tz in an in vivo infection model, whereas it remained inactive and non-harmful without the chemical trigger. This study constitutes the first example of a systemically acting two-component antibiotic with improved drug tolerability.
AB - The use of highly potent but very toxic antibiotics such as colistin has become inevitable due to the rise of antimicrobial resistance. We aimed for a chemically-triggered, controlled release of colistin at the infection site to lower its systemic toxicity by harnessing the power of click-to-release reactions. Kinetic experiments with nine tetrazines and three dienophiles demonstrated a fast release via an inverse-electron-demand Diels–Alder reaction between trans-cyclooctene (TCO) and the amine-functionalised tetrazine Tz7. The antibiotic activity of colistin against Escherichia coli was masked by TCO units, but restored upon reaction with d-Ubi−Tz, a tetrazine functionalised with the bacterial binding peptide d-Ubi29–41. While standard TCO did not improve toxicity against human proximal tubular kidney HK-2 cells, the installation of an aspartic acid-modified TCO masking group reduced the overall charge of the peptide and entry to the kidney cells, thereby dramatically lowering its toxicity. The analog Col−(TCO-Asp)1 had favourable pharmacokinetic properties in mice and was successfully activated locally in the lung by d-Ubi−Tz in an in vivo infection model, whereas it remained inactive and non-harmful without the chemical trigger. This study constitutes the first example of a systemically acting two-component antibiotic with improved drug tolerability.
KW - antibiotics
KW - bioorthogonal chemistry
KW - drug conjugates
KW - drug delivery
KW - natural products
UR - http://www.scopus.com/inward/record.url?scp=85206569302&partnerID=8YFLogxK
U2 - 10.1002/anie.202408360
DO - 10.1002/anie.202408360
M3 - Article
C2 - 39113573
AN - SCOPUS:85206569302
VL - 63
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
SN - 1433-7851
IS - 47
M1 - e202408360
ER -