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<p>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.</p>

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Cystobactamid off-target profiling reveals favorable safety, superoxide reduction, and SCARB1 inhibition in eukaryotes

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月6日

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  • 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

摘要

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.