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

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.

SUBMITTER: Paterson DJ

PROVIDER: S-EPMC5635876 | biostudies-other | 2017 Oct

REPOSITORIES: biostudies-other

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

Paterson David J DJ Tassieri Manlio M Reboud Julien J Wilson Rab R Cooper Jonathan M JM

Proceedings of the National Academy of Sciences of the United States of America 20170920 40

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 ...[more]

PMID: 28931578

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Dataset Information

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

Publications

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

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