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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

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author He Runze, Di Bonaventura Ivan, Visini Ricardo, Gan Bee Ha, Fu Yongchun, Probst Daniel, Lüscher Alexandre, Köhler Thilo, van Delden Christian, Stocker Achim, Hong Wenjing, Darbre Tamis, Reymond Jean-Louis,
Project A Chemical Space Approach to Bioactive Peptides
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Original article (peer-reviewed)

Journal Chemical Science
Volume (Issue) 8
Page(s) 7464 - 7475
Title of proceedings Chemical Science
DOI 10.1039/c7sc01599b

Open Access

Type of Open Access Publisher (Gold Open Access)


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.