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Lookup NU author(s): Dr Nico Paracini, Professor Jeremy LakeyORCiD
This is the authors' accepted manuscript of an article that has been published in its final definitive form by National Academy of Sciences, 2018.
For re-use rights please refer to the publisher's terms and conditions.
The outer membrane (OM) of Gram-negative bacteria is a robust, impermeable, asymmetric bilayer of outer lipopolysaccharides (LPS) and inner phospholipids containing selective pore proteins which confer on it the properties of a molecular sieve. This structure severely limits the variety of antibiotic molecules effective against Gram-negative pathogens and as antibiotic resistance has increased so has the need to solve the OM permeability problem. Polymyxin B (PmB) represents those rare antibiotics which act directly on the OM and which offer a distinct starting point for new antibiotic development. Here we investigate PmB’s interactions with in vitro OM models and show how the physical state of the lipid matrix of the OM is a critical factor in regulating the interaction with the antimicrobial peptide. Using neutron reflectometry and infrared spectroscopy, we reveal the structural and chemical changes induced by PmB on OM models of increasing complexity. In particular only a tightly packed model reproduced the temperature controlled disruption of the asymmetric lipid bilayer by PmB observed in vivo. By measuring the order of outer leaflet LPS and inner leaflet phospholipids we show that PmB insertion is dependent on the phase transition of LPS from the gel to the liquid crystalline state. The demonstration of a lipid phase transition in the physiological temperature range also supports the hypothesis that bacteria grown at different temperatures adapt their LPS structures to maintain a homeoviscous OM.
Author(s): Paracini N, Clifton LA, Skoda MWA, Lakey JH
Publication type: Article
Publication status: Published
Journal: Proceedings of the National Academy of Sciences of the United States of America
Year: 2018
Volume: 115
Issue: 32
Pages: E7587-E7594
Print publication date: 07/08/2018
Online publication date: 23/07/2018
Acceptance date: 02/04/2018
Date deposited: 27/06/2018
ISSN (print): 0027-8424
ISSN (electronic): 1091-6490
Publisher: National Academy of Sciences
URL: https://doi.org/10.1073/pnas.1803975115
DOI: 10.1073/pnas.1803975115
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