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<p>Zosurabalpin, a novel tethered macrocyclic peptide antibiotic, exhibits potent activity against <i>Acinetobacter</i> spp., particularly carbapenem-resistant <i>Acinetobacter baumannii</i> (CRAB). Zosurabalpin inhibits lipopolysaccharide (LPS) transport by targeting the LptB2FG protein complex, resulting in toxic LPS accumulation and bacterialdeath. This study investigates zosurabalpin’s molecular specificity against <i>Acinetobacter</i> spp., its ineffectiveness against <i>Klebsiella pneumoniae</i>, and its potential efficacy against <i>Shigella flexneri</i>. Comparative analysis of LptB2FG sequences and structures, revealed significant differences in LptB2FG protein conformations, pocket geometry and electrostatic surface surrounding the binding pocket among the three species, which may influence zosurabalpin binding. Docking results for zosurabalpin showed lower binding affinities for <i>K. pneumoniae</i> and <i>S. flexneri</i> compared to <i>Acinetobacter baylyi</i>. Additionally, other zosurabalpin derivatives were tested showing improved binding affinities for <i>K. pneumoniae</i> but not for <i>S. flexneri</i>. These findings underscore the need for tailored zosurabalpin derivatives to enhance efficacy against a broader spectrum of Gram-negative bacteria.</p>

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In silico analysis of zosurabalpin-LptB2FG binding in Acinetobacter spp., Klebsiella pneumoniae, and Shigella flexneri: mechanisms underlying its differential efficacy

  • 期刊论文

  • 发表日期：

    2025年4月16日

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  • Meryam Magri,
  • Rachid Eljaoudi,
  • Lahcen Belyamani,
  • Azeddine Ibrahimi,
  • El Mehdi Bouricha

摘要

Zosurabalpin, a novel tethered macrocyclic peptide antibiotic, exhibits potent activity against Acinetobacter spp., particularly carbapenem-resistant Acinetobacter baumannii (CRAB). Zosurabalpin inhibits lipopolysaccharide (LPS) transport by targeting the LptB2FG protein complex, resulting in toxic LPS accumulation and bacterialdeath. This study investigates zosurabalpin’s molecular specificity against Acinetobacter spp., its ineffectiveness against Klebsiella pneumoniae, and its potential efficacy against Shigella flexneri. Comparative analysis of LptB2FG sequences and structures, revealed significant differences in LptB2FG protein conformations, pocket geometry and electrostatic surface surrounding the binding pocket among the three species, which may influence zosurabalpin binding. Docking results for zosurabalpin showed lower binding affinities for K. pneumoniae and S. flexneri compared to Acinetobacter baylyi. Additionally, other zosurabalpin derivatives were tested showing improved binding affinities for K. pneumoniae but not for S. flexneri. These findings underscore the need for tailored zosurabalpin derivatives to enhance efficacy against a broader spectrum of Gram-negative bacteria.