Inhibition and dispersion of Pseudomonas aeruginosa biofilms by glycopeptide dendrimers targeting the fucose-specific lectin LecB.
The human pathogenic bacterium Pseudomonas aeruginosa produces a fucose-specific lectin, LecB, implicated in tissue attachment and the formation of biofilms. To investigate if LecB inhibition disrupts these processes, high-affinity ligands were obtained by screening two 15,536-member combinatorial libraries of multivalent fucosyl-peptide dendrimers. The most potent LecB-ligands identified were dendrimers FD2 (C-Fuc-LysProLeu)(4)(LysPheLysIle)(2)LysHisIleNH(2) (IC(50) = 0.14 microM by ELLA) and PA8 (OFuc-LysAlaAsp)(4)(LysSerGlyAla)(2)LysHisIleNH(2) (IC(50) = 0.11 microM by ELLA). Dendrimer FD2 led to complete inhibition of P. aeruginosa biofilm formation (IC(50) approximately 10 microM) and induced complete dispersion of established biofilms in the wild-type strain and in several clinical P. aeruginosa isolates. These experiments suggest that LecB inhibition by high-affinity multivalent ligands could represent a therapeutic approach against P. aeruginosa infections by inhibition of biofilm formation and dispersion of established biofilms.
Johansson
Emma M V
EM
Department of Chemistry and Biochemistry, University of Berne, Freiestrasse 3, CH-3012 Berne, Switzerland.
Crusz
Shanika A
SA
Kolomiets
Elena
E
Buts
Lieven
L
Kadam
Rameshwar U
RU
Cacciarini
Martina
M
Bartels
Kai-Malte
KM
Diggle
Stephen P
SP
Cámara
Miguel
M
Williams
Paul
P
Loris
Remy
R
Nativi
Cristina
C
Rosenau
Frank
F
Jaeger
Karl-Erich
KE
Darbre
Tamis
T
Reymond
Jean-Louis
JL
D000595:Amino Acid Sequence; D001422:Bacterial Adhesion / Q000187:drug effects; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism; D018441:Biofilms / Q000187:drug effects*; D050091:Dendrimers / Q000737:chemistry* / Q000494:pharmacology; D016503:Drug Delivery Systems; D005643:Fucose / Q000737:chemistry / Q000378:metabolism; D006020:Glycopeptides / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D037102:Lectins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
D001425:Bacterial Outer Membrane Proteins; D050091:Dendrimers; C534598:FD2 dendrimer; D006020:Glycopeptides; C534600:LecB protein, Pseudomonas aeruginosa; D037102:Lectins; D008024:Ligands; C534599:PA8 dendrimer; D005643:Fucose