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Disruption of drug-resistant biofilms using de novo designed short α-helical antimicrobial peptides with idealized facial amphiphilicity

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Title: Disruption of drug-resistant biofilms using de novo designed short α-helical antimicrobial peptides with idealized facial amphiphilicity
Authors: Khara, JS
Obuobi, S
Wang, Y
Hamilton, MS
Robertson, BD
Newton, SM
Yang, YY
Langford, PR
Ee, PLR
Item Type: Journal Article
Abstract: The escalating threat of antimicrobial resistance has increased pressure to develop novel therapeutic strategies to tackle drug-resistant infections. Antimicrobial peptides have emerged as a promising class of therapeutics for various systemic and topical clinical applications. In this study, the de novo design of α-helical peptides with idealized facial amphiphilicities, based on an understanding of the pertinent features of protein secondary structures, is presented. Synthetic amphiphiles composed of the backbone sequence (X1Y1Y2X2)n, where X1 and X2 are hydrophobic residues (Leu or Ile or Trp), Y1 and Y2 are cationic residues (Lys), and n is the number repeat units (2 or 2.5 or 3), demonstrated potent broad-spectrum antimicrobial activities against clinical isolates of drug-susceptible and multi-drug resistant bacteria. Live-cell imaging revealed that the most selective peptide, (LKKL)3, promoted rapid permeabilization of bacterial membranes. Importantly, (LKKL)3 not only suppressed biofilm growth, but effectively disrupted mature biofilms after only 2 h of treatment. The peptides (LKKL)3 and (WKKW)3 suppressed the production of LPS-induced pro-inflammatory mediators to levels of unstimulated controls at low micromolar concentrations. Thus, the rational design strategies proposed herein can be implemented to develop potent, selective and multifunctional α-helical peptides to eradicate drug-resistant biofilm-associated infections.
Issue Date: 29-Apr-2017
Date of Acceptance: 19-Apr-2017
URI: http://hdl.handle.net/10044/1/48232
DOI: https://dx.doi.org/10.1016/j.actbio.2017.04.032
ISSN: 1878-7568
Publisher: Elsevier
Start Page: 103
End Page: 114
Journal / Book Title: Acta Biomaterialia
Volume: 57
Copyright Statement: © 2017 Acta Materialia Inc. Published by Elsevier Ltd. This is an open access article underthe CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Sponsor/Funder: British Society for Antimicrobial Chemotherapy
National Medical Res. Council
British Society of Antimicrobial Chemotherapy
British Society for Antimicrobial Chemotherapy
Funder's Grant Number: GA2011-01P
RL2012-001
GA2016_009P
GA2016_009P
Keywords: Alpha-helix
Anti-endotoxic
Antimicrobial peptides (AMPs)
Drug-resistant biofilms
Ideal facial amphiphilicity
Biomedical Engineering
MD Multidisciplinary
Publication Status: Published
Appears in Collections:Department of Medicine (up to 2019)