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bioRxiv · 10.64898/2026.08.24.746625

Outer membrane stiffness gates multidrug tolerance

Xiao, N.·Zheng, B.·Liu, J.-F.
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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.

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Xiao, N., Zheng, B., Liu, J.-F.. 2026-08-24. Outer membrane stiffness gates multidrug tolerance. https://doi.org/10.64898/2026.08.24.746625

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