Outer membrane stiffness gates multidrug tolerance

Authors

Xiao, N., Zheng, B., Liu, J.-F.

Abstract

Bactericidal antibiotics initiate killing through class-specific target damage, yet the cellular properties that determine whether antibiotic-induced damage remains reversible or progresses to irreversible death remains unclear. Here, using kanamycin-centered evolution in Escherichia coli, we identified a multidrug-tolerant mutant that exhibits increased survival across aminoglycosides, {beta}-lactams, quinolones and polymyxins without altered minimum inhibitory concentrations. We demonstrate that mechanistically distinct antibiotics converge on outer membrane destabilization, revealing a shared downstream vulnerability during killing. Elevated outer membrane stiffness limits antibiotic-induced envelope destabilization, thereby gating multidrug tolerance. Orthogonal chemical and physical perturbations further established a quantitative relationship between outer membrane stiffness and antibiotic survival across drug classes. Our findings reveal outer membrane stiffness as a previously unrecognized physical basis of multidrug tolerance and suggest that modulating bacterial envelope mechanics may provide new opportunities for antimicrobial intervention.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 25 Aug 2026.

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