Authors
Timo Risch, Benedikt Hellwinkel, Dietrich Mostert, Andreas M Kany, Danny Solga, Tim Seedorf, Dominik Heimann, Jessica Hoppstädter, Daniel Kohnhäuser, Jil-Sophie Hilgers, Franziska Fries, Felix Deschner, Mark Brönstrup, Andreas Kirschning, Stephan A Sieber, Thomas Pietschmann, Alexandra K Kiemer, Jennifer Herrmann, Rolf Müller
Published in
npj drug discovery. Volume 2. Issue 1. Aug 06, 2025. Epub Aug 06, 2025.
Abstract
Antimicrobial resistance poses a fundamental global threat, necessitating new strategies for effective therapies. Cystobactamids, a class of antibacterial agents targeting bacterial gyrase and topoisomerase IV, represent a non-traditional chemical scaffold with broad-spectrum activity. For toxicological de-risking, we performed a comprehensive profiling on eukaryotic cells, focusing on cytotoxicity, genotoxicity, and mitochondrial toxicity, demonstrating cellular safety and superoxide scavenging properties. Studies in zebrafish embryos assessed developmental, cardiovascular, and hepatic toxicity, indicating a favorable in vivo safety profile. Metabolism studies revealed glucuronidation and amide bond hydrolysis as key pathways, whereby cystobactamid metabolic stability substantially improved by cobicistat co-treatment. Affinity-based protein profiling identified the cholesterol- and HCV-receptor scavenger receptor class B member 1 (SCARB1) as a primary eukaryotic off-target protein, with cystobactamids shown to inhibit SCARB1´s function, preventing hepatitis C virus pseudoparticle entry into cells. These findings suggest a high therapeutic potential for cystobactamids and highlight SCARB1 as a primary eukaryotic target.
PMID:
42380264
Bibliographic data and abstract were imported from PubMed on 01 Jul 2026.
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