In this section
@article{Edwards:2025,
author = {Edwards, A and Borrelli, C and Douglas, E and Riley, S and Lemonidi, E and Larrouy-Maumus, G and Lu, W-J and Bonev, B and Hoogenboom, B},
journal = {Nature Microbiology},
title = {Polymyxin B lethality requires energy-dependent outer membrane disruption},
year = {2025}
}
TY - JOUR
AB - 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 from the outer membrane (OM), and a corresponding reduction in barrier function, processes that required LPS synthesis and transport, but were blocked by the MCR-1 polymyxin resistance determinant. 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. This work reveals how metabolic inactivity confers tolerance of a clinically important, membrane-targeting antibiotic, leading to new insight into mechanism of action.
AU - Edwards,A
AU - Borrelli,C
AU - Douglas,E
AU - Riley,S
AU - Lemonidi,E
AU - Larrouy-Maumus,G
AU - Lu,W-J
AU - Bonev,B
AU - Hoogenboom,B
PY - 2025///
SN - 2058-5276
TI - Polymyxin B lethality requires energy-dependent outer membrane disruption
T2 - Nature Microbiology
ER -
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