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.

Risch, Timo, Benedikt Hellwinkel, Dietrich Mostert, Andreas M. Kany, Danny Solga, Tim Seedorf, Dominik Heimann et al. "Cystobactamid off-target profiling reveals favorable safety, superoxide reduction, and SCARB1 inhibition in eukaryotes." npj Drug Discovery 2(1), 20 (2025).

Link: https://doi.org/10.1038/s44386-025-00020-7

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