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

Fabian Munder1,2,3, Matthew D Johnson2,3, Imogen Samuels3

  • 1Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.

Nature Communications
|July 2, 2026
PubMed

Insights

New protein antibiotics, L-type pyocins, kill Pseudomonas aeruginosa by targeting the cell surface’s β-barrel assembly machinery (BAM) complex. This discovery offers a novel strategy for developing effective antibiotics against challenging Gram-negative pathogens.

Area of Science:

  • Microbiology
  • Structural Biology
  • Drug Discovery

Background:

  • Gram-negative bacteria like Pseudomonas aeruginosa possess a challenging outer membrane barrier limiting antibiotic efficacy.
  • The β-barrel assembly machinery (BAM) complex is crucial for assembling outer membrane proteins in Gram-negative bacteria.

Purpose of the Study:

  • To investigate the mechanism of action of L-type pyocins against Pseudomonas aeruginosa.
  • To explore the potential of targeting the BAM complex as a novel antibiotic strategy.

Main Methods:

  • Single-particle cryo-electron microscopy to determine the structure of L-type pyocins bound to BamA.
  • Genetics, multi-omics (transcriptomics, proteomics), and cryo-electron tomography to analyze the cellular response to BAM inhibition.
  • In vitro assays to assess antibiotic activity and mechanism.

Main Results:

  • L-type pyocins inhibit the BAM complex at the cell surface by targeting BamA, without requiring cell entry.
  • BAM complex inhibition by L-type pyocins or darobactin triggers significant transcriptomic, proteomic, and morphological changes.
  • Inhibition of the BAM complex leads to loss of membrane integrity and cell death.

Conclusions:

  • The BAM complex is a validated target for antibiotics that act extracellularly.
  • L-type pyocins represent a promising class of antibiotics effective against Pseudomonas aeruginosa.
  • This study defines an engineerable system for developing novel antibiotics targeting the BAM complex.

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