Issue 11, 2017

Design, crystal structure and atomic force microscopy study of thioether ligated d,l-cyclic antimicrobial peptides against multidrug resistant Pseudomonas aeruginosa

Abstract

Here we report a new family of cyclic antimicrobial peptides (CAMPs) targeting MDR strains of Pseudomonas aeruginosa. These CAMPs are cyclized via a xylene double thioether bridge connecting two cysteines placed at the ends of a linear amphiphilic alternating D,L-sequence composed of lysines and tryptophans. Investigations by transmission electron microscopy (TEM), dynamic light scattering and atomic force microscopy (AFM) suggest that these peptide macrocycles interact with the membrane to form lipid–peptide aggregates. Amphiphilic conformations compatible with membrane disruption are observed in high resolution X-ray crystal structures of fucosylated derivatives in complex with lectin LecB. The potential for optimization is highlighted by N-methylation of backbone amides leading to derivatives with similar antimicrobial activity but lower hemolysis.

Graphical abstract: Design, crystal structure and atomic force microscopy study of thioether ligated d,l-cyclic antimicrobial peptides against multidrug resistant Pseudomonas aeruginosa

Supplementary files

Article information

Article type
Edge Article
Submitted
10 Apr 2017
Accepted
02 Sep 2017
First published
04 Sep 2017
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2017,8, 7464-7475

Design, crystal structure and atomic force microscopy study of thioether ligated D,L-cyclic antimicrobial peptides against multidrug resistant Pseudomonas aeruginosa

R. He, I. Di Bonaventura, R. Visini, B. Gan, Y. Fu, D. Probst, A. Lüscher, T. Köhler, C. van Delden, A. Stocker, W. Hong, T. Darbre and J. Reymond, Chem. Sci., 2017, 8, 7464 DOI: 10.1039/C7SC01599B

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