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Lookup NU author(s): Dr Nico Paracini, Professor Jeremy LakeyORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2025 The Authors. Published by American Chemical Society. The lipid matrix of the outer membrane (OM) of Gram-negative bacteria consists of a highly asymmetric lipid bilayer containing phospholipids on the inner leaflet and lipopolysaccharides (LPS) in the outer layer. The latter ensures that harmful molecules do not permeate the bacterial cell, but polymyxin B (PmB), a last-resort antibiotic, is capable of interfering with the stability of the LPS layer and overcoming the OM barrier. We have previously shown that the efficacy of PmB in disrupting isotopically asymmetric OM models (2H-phospholipids and 1H-LPS) is regulated by the gel-to-fluid phase transition of the LPS layer. Here, we employ fully deuterated OM models (2H-phospholipids and 2H-LPS) to track the temperature-dependent penetration of PmB within the model membrane by using neutron reflectometry. We use a model-independent approach to quantify PmB penetration as a function of both concentration and temperature as well as a model-dependent analysis to localize PmB in the asymmetric bilayer. By leveraging the ability of neutrons to differentiate hydrogen from deuterium in structural biology we find that PmB hijacks LPS molecules and accumulates predominantly in the hydrophobic region of lipid A.
Author(s): Paracini N, Lakey JH, Clifton LA
Publication type: Article
Publication status: Published
Journal: ACS Omega
Year: 2025
Volume: 10
Issue: 3
Pages: 2616-2627
Print publication date: 28/01/2025
Online publication date: 14/01/2025
Acceptance date: 18/12/2024
Date deposited: 03/02/2025
ISSN (electronic): 2470-1343
Publisher: American Chemical Society
URL: https://doi.org/10.1021/acsomega.4c07648
DOI: 10.1021/acsomega.4c07648
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