Lipid topology and electrostatic interactions underpin lytic activity of linear cationic antimicrobial peptides in membranes

Paterson, D. J., Tassieri, M. , Reboud, J. , Wilson, R. and Cooper, J. M. (2017) Lipid topology and electrostatic interactions underpin lytic activity of linear cationic antimicrobial peptides in membranes. Proceedings of the National Academy of Sciences of the United States of America, 114(40), E8324-E8332. (doi:10.1073/pnas.1704489114) (PMID:28931578)

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Abstract

Linear cationic antimicrobial peptides are a diverse class of molecules that interact with a wide range of cell membranes. Many of these peptides disrupt cell integrity by forming membrane-spanning pores that ultimately lead to their death. Despite these peptides high potency and ability to evade acquired bacterial drug resistance, there is a lack of knowledge on their selectivity and activity mechanisms. Such an understanding would provide an informative framework for rational design and could lead to potential antimicrobial therapeutic targets. In this paper, we use a high-throughput microfluidic platform as a quantitative screen to assess peptide activity and selectivity by precisely controlling exposure to vesicles with lipid compositions that mimic both bacterial and mammalian cell membranes. We explore the complexity of the lipid–peptide interactions governing membrane-disruptive behaviors and establish a link between peptide pore formation and both lipid–peptide charge and topological interactions. We propose a topological model for linear antimicrobial peptide activity based on the increase in membrane strain caused by the continuous adsorption of peptides to the target vesicle coupled with the effects of both lipid–peptide charge and topographical interactions. We also show the validity of the proposed model by investigating the activity of two prototypical linear cationic peptides: magainin 2 amide (which is selective for bacterial cells) and melittin (which targets both mammalian and bacterial cells indiscriminately). Finally, we propose the existence of a negative feedback mechanism that governs the pore formation process and controls the membrane’s apparent permeability.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Wilson, Dr Robert and Cooper, Professor Jonathan and Tassieri, Dr Manlio and Reboud, Dr Julien and Paterson, Mr David
Authors: Paterson, D. J., Tassieri, M., Reboud, J., Wilson, R., and Cooper, J. M.
College/School:College of Science and Engineering > School of Engineering > Biomedical Engineering
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):1091-6490
Published Online:20 September 2017
Copyright Holders:Copyright © 2017 National Academy of Sciences
First Published:First published in Proceedings of the National Academy of Sciences of the United States of America 114(40):E8324-E8332
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
470561DTC in cell and proteomic technologies (continuation)Jonathan CooperEngineering and Physical Sciences Research Council (EPSRC)EP/F500424/1ENG - BIOMEDICAL ENGINEERING
553521Next Generation Analytical Tools: Application to Protein Oxidations that affect Human Health and WellbeingJonathan CooperEngineering and Physical Sciences Research Council (EPSRC)EP/I017887/1ENG - BIOMEDICAL ENGINEERING
621351Synthetic Biology applications to Water Supply and RemediationSteven BeaumontEngineering and Physical Sciences Research Council (EPSRC)EP/K038885/1VPO VICE PRINCIPAL RESEARCH & ENTERPRISE
617021Advanced Diagnostics using PhononicsJonathan CooperEngineering and Physical Sciences Research Council (EPSRC)EP/K027611/1ENG - BIOMEDICAL ENGINEERING
534472Rheology at the Microscale: New Tools for Bio-analysisManlio TassieriEngineering and Physical Sciences Research Council (EPSRC)10216/101ENG - BIOMEDICAL ENGINEERING