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

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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

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Publication details

The article was received on 10 Apr 2017, accepted on 02 Sep 2017 and first published on 04 Sep 2017


Article type: Edge Article
DOI: 10.1039/C7SC01599B
Citation: Chem. Sci., 2017, Advance Article
  • Open access: Creative Commons BY-NC license
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    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, Advance Article , DOI: 10.1039/C7SC01599B

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