A Targeted Click-to-Release Activation of the Last-Resort Antibiotic Colistin Reduces its Renal Cell Toxicity

verfasst von: Jiraborrirak Charoenpattarapreeda, Werner Tegge, Chunfa Xu, Kirsten Harmrolfs, Bettina Hinkelmann, Hannah Wullenkord, Sven Kevin Hotop, Ulrike Beutling, Katharina Rox, Mark Brönstrup
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-Ubi_29–41. 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.
Organisationseinheit(en): Zentrum für Biomolekulare Wirkstoffe (BMWZ)
Externe Organisation(en): Helmholtz-Zentrum für Infektionsforschung GmbH (HZI)
Deutsches Zentrum für Infektionsforschung (DZIF)
Typ: Artikel
Journal: Angewandte Chemie - International Edition
Band: 63
Anzahl der Seiten: 8
ISSN: 1433-7851
Publikationsdatum: 11.11.2024
Publikationsstatus: Veröffentlicht
Peer-reviewed: Ja
ASJC Scopus Sachgebiete: Katalyse, Allgemeine Chemie
Elektronische Version(en): https://doi.org/10.1002/anie.202408360 (Zugang: Offen)

BibTeX

@article{f84b7ba4e5d34ffaaa886409c2a20c1f,
title = "A Targeted Click-to-Release Activation of the Last-Resort Antibiotic Colistin Reduces its Renal Cell Toxicity",
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.",
keywords = "antibiotics, bioorthogonal chemistry, drug conjugates, drug delivery, natural products",
author = "Jiraborrirak Charoenpattarapreeda and Werner Tegge and Chunfa Xu and Kirsten Harmrolfs and Bettina Hinkelmann and Hannah Wullenkord and Hotop, {Sven Kevin} and Ulrike Beutling and Katharina Rox and Mark Br{\"o}nstrup",
note = "Publisher Copyright: {\textcopyright} 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.",
year = "2024",
month = nov,
day = "11",
doi = "10.1002/anie.202408360",
language = "English",
volume = "63",
journal = "Angewandte Chemie - International Edition",
issn = "1433-7851",
publisher = "John Wiley and Sons Ltd",
number = "47",
}