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<p>Many antibiotics are ineffective against the Gram-negative pathogen <i>Pseudomonas aeruginosa</i> because of intrinsic defence mechanisms, such as the impermeable bacterial outer membrane. Here, we show that protein antibiotics called L-type pyocins kill <i>P. aeruginosa</i> by inhibiting the β-barrel assembly machinery (BAM) complex at the cell surface, halting outer-membrane protein assembly. Using single-particle cryo-electron microscopy, we show that L-type pyocins bind a surface-exposed region of BamA and deploy a C-terminal peptide that competitively inhibits the BAM complex, demonstrating that cell entry is not required for antibiotic activity. We combine genetics, multi-omics and cryo-electron tomography to show that BAM complex inhibition by L-type pyocins or the cyclic-peptide antibiotic, darobactin, triggers a multifaceted transcriptomic, proteomic, and morphological response. BAM inhibition ultimately leads to a catastrophic loss of membrane integrity and cell death. These results validate BAM as a target for antibiotics that do not enter the cell and define an engineerable system for their development.</p>

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L-type pyocins inhibit the BAM complex to kill without cell entry

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月2日

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  • Fabian Munder,
  • Matthew D. Johnson,
  • Imogen Samuels,
  • Laura McCaughey,
  • Oleksii Zdorevskyi,
  • Chunxiao Wang,
  • Ashleigh Kropp,
  • Lauren Zavan,
  • Erin P. Price,
  • Derek S. Sarovich,
  • Swati Varshney,
  • Christopher A. McDevitt,
  • Hari Venugopal,
  • Vivek Sharma,
  • Matthew T. Doyle,
  • Francesca Short,
  • Debnath Ghosal,
  • James P. R. Connolly,
  • Gavin J. Knott,
  • Rhys Grinter

摘要

Many antibiotics are ineffective against the Gram-negative pathogen Pseudomonas aeruginosa because of intrinsic defence mechanisms, such as the impermeable bacterial outer membrane. Here, we show that protein antibiotics called L-type pyocins kill P. aeruginosa by inhibiting the β-barrel assembly machinery (BAM) complex at the cell surface, halting outer-membrane protein assembly. Using single-particle cryo-electron microscopy, we show that L-type pyocins bind a surface-exposed region of BamA and deploy a C-terminal peptide that competitively inhibits the BAM complex, demonstrating that cell entry is not required for antibiotic activity. We combine genetics, multi-omics and cryo-electron tomography to show that BAM complex inhibition by L-type pyocins or the cyclic-peptide antibiotic, darobactin, triggers a multifaceted transcriptomic, proteomic, and morphological response. BAM inhibition ultimately leads to a catastrophic loss of membrane integrity and cell death. These results validate BAM as a target for antibiotics that do not enter the cell and define an engineerable system for their development.