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Issue 1, 2016
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Overcoming antibiotic resistance in Pseudomonas aeruginosa biofilms using glycopeptide dendrimers

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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.

Graphical abstract: Overcoming antibiotic resistance in Pseudomonas aeruginosa biofilms using glycopeptide dendrimers

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Supplementary files

Article information


Submitted
24 Sep 2015
Accepted
23 Nov 2015
First published
25 Nov 2015

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2016,7, 166-182
Article type
Edge Article
Author version available

Overcoming antibiotic resistance in Pseudomonas aeruginosa biofilms using glycopeptide dendrimers

G. Michaud, R. Visini, M. Bergmann, G. Salerno, R. Bosco, E. Gillon, B. Richichi, C. Nativi, A. Imberty, A. Stocker, T. Darbre and J. Reymond, Chem. Sci., 2016, 7, 166
DOI: 10.1039/C5SC03635F

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    [Original citation] - Published by The Royal Society of Chemistry.

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