Polymyxin B lethality requires energy-dependent outer membrane disruption
File(s)
Preprint version
Author(s)
Borrelli, Carolina
Douglas, Edward JA
Riley, Sophia MA
Lemonidi, Aikaterini Ellas
Larrouy-Maumus, Gerald
Type
preprint
Abstract
Polymyxin antibiotics target lipopolysaccharide (LPS) in both membranes of the bacterial cell envelope, leading to bacterial killing through a mechanism that remains poorly understood. Here, we demonstrate that metabolic activity is essential for polymyxin lethality and leverage this insight to determine its mode of action. Polymyxin B (PmB) efficiently killed exponential phase E. coli but was unable to eliminate stationary phase cells unless a carbon source was available. Antibiotic lethality correlated with surface protrusions, LPS loss, and a significant reduction in outer membrane (OM) barrier function, processes that required LPS synthesis and transport. While the energy-dependent OM disruption was not directly lethal, it facilitated PmB access to the inner membrane (IM), which the antibiotic permeabilised in an energy-independent manner, leading to cell death. Finally, we show that the polymyxin resistance determinant MCR-1 prevents PmB-mediated LPS loss and OM protrusions and thereby renders the antibiotic ineffective. .
Date Issued
2025-04-16
Citation
bioRxiv, 2025
Journal / Book Title
BioRxiv
Copyright Statement
Copyright © 2025 The Authors. This work is licensed under a Creative Commons Attribution 4.0 International License.
License URL
Description
Preprint version
Identifier
10.1101/2025.04.16.649083