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Overcoming antibiotic resistance in Pseudomonas aeruginosa biofilms using glycopeptide dendrimers

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Michaud Gaëlle, Visini Ricardo, Bergmann Myriam, Salerno Gianluca, Bosco Rosa, Gillon Emilie, Richichi Barbara, qNativi Cristina, Imberty Anne, Stocker Achim, 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) 7
Page(s) 166 - 182
Title of proceedings Chemical Science
DOI 10.1039/c5sc03635f

Open Access

Abstract

Antibiotic resistance in the opportunistic pathogen Pseudomonas aeruginosa is partly caused by biofilms forming a physical barrier to antibiotic penetration. Here we focused on modifying tetravalent glycopeptide dendrimer ligands of P. aeruginosa lectins LecB or LecA to increase their biofilm inhibition activity. First heteroglycoclusters were investigated displaying one pair each of LecB specific fucosyl groups and LecA specific galactosyl groups and binding simultaneously to both lectins, one of which gave the first fully resolved crystal structure of a peptide dendrimer as LecB complex providing a structural model for dendrimer–lectin interactions (PDB 5D2A). Biofilm inhibition was increased by introducing additional cationic residues in these dendrimers but resulted in bactericidal effects similar to those of non-glycosylated polycationic antimicrobial peptide dendrimers. In a second approach dendrimers displaying four copies of the natural LecB ligand Lewisa were prepared leading to slightly stronger LecB binding and biofilm inhibition. Finally synergistic application of a LecB specific non-bactericidal antibiofilm dendrimer with the antibiotic tobramycin at sub-inhibitory concentrations of both compounds allowed effective biofilm inhibition and dispersal.
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