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

Summary

This work demonstrates that L-type pyocins kill Pseudomonas aeruginosa by surface inhibition of the BAM complex, obviating the need for cell entry. Structural and multi-omics data validate BAM as an antibiotic target and establish an engineerable protein antibiotic platform.

Key Findings

• L-type pyocins bind a surface-exposed region of BamA and competitively inhibit the BAM complex, halting outer-membrane protein assembly.
• Single-particle cryo-EM and cryo-ET define the inhibitory interaction and downstream morphological consequences.
• BAM inhibition by L-type pyocins or darobactin elicits coherent transcriptomic and proteomic stress responses, culminating in membrane failure and cell death.
• Validates BAM as a non-entry antibiotic target and delineates an engineerable protein antibiotic system.

Clinical Implications

BAM-targeting biologics or engineered L-type pyocins may offer new therapeutics for multidrug-resistant P. aeruginosa in respiratory infections (e.g., bronchiectasis, cystic fibrosis), potentially bypassing outer-membrane permeability barriers.

Limitations

• Preclinical; in vivo efficacy, pharmacokinetics, and immunogenicity in mammalian respiratory models remain to be established.
• Potential for resistance evolution against BAM-targeting agents requires systematic assessment.

Future Directions

Engineer L-type pyocins for enhanced stability and delivery; assess efficacy in airway infection models; map resistance liabilities; explore synergy with conventional antibiotics.