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TitleL-type pyocins inhibit the BAM complex to kill without cell entry.
Journal, issue, pagesNat Commun, Year 2026
Publish dateJul 2, 2026
AuthorsFabian 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 /
PubMed AbstractMany 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 ...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.
External linksNat Commun / PubMed:42393045
MethodsEM (single particle)
Resolution2.75 - 3.18 Å
Structure data

71969

9pxg

EMDB-71969, PDB-9pxg:
Cryo-EM structure of apo BAM from P. aeruginosa PAO1
Method: EM (single particle) / Resolution: 2.75 Å

71970

9pxi

EMDB-71970, PDB-9pxi:
Cryo-EM structure of BAM from P. aeruginosa PAO1 in complex with Pyocin L1
Method: EM (single particle) / Resolution: 2.85 Å

71971

9pxj

EMDB-71971, PDB-9pxj:
Cryo-EM structure of BAM from P. aeruginosa P28 in complex with Pyocin L2
Method: EM (single particle) / Resolution: 3.18 Å

Chemicals

ChemComp-NA:
Unknown entry

Source
  • pseudomonas aeruginosa (bacteria)
  • pseudomonas aeruginosa pao1 (bacteria)
  • pseudomonas aeruginosa 62 (bacteria)
KeywordsMEMBRANE PROTEIN / protein complex / outer membrane / beta-barrel / protein folding / Gram-negative bacterial protein / L-type bacteriocin / pyocin

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