Multivalency effects on Pseudomonas aeruginosa biofilm inhibition and dispersal by glycopeptide dendrimers targeting lectin LecA

Abstract

The galactose specific lectin LecA partly mediates the formation of antibiotic resistant biofilms by Pseudomonas aeruginosa, an opportunistic pathogen causing lethal airways infections in immunocompromised and cystic fibrosis patients, suggesting that preventing LecA binding to natural saccharides might provide new opportunities for treatment. Here 8-fold (G3) and 16-fold (G4) galactosylated analogs of GalAG2, a tetravalent G2 glycopeptide dendrimer LecA ligand and P. aeruginosa biofilm inhibitor, were obtained by convergent chloroacetyl thioether (ClAc) ligation between 4-fold or 8-fold chloroacetylated dendrimer cores and digalactosylated dendritic arms. Hemagglutination inhibition, isothermal titration calorimetry and biofilm inhibition assays showed that G3 dendrimers bind LecA slightly better than their parent G2 dendrimers and induce complete biofilm inhibition and dispersal of P. aeruginosa biofilms, while G4 dendrimers show reduced binding and no biofilm inhibition. A binding model accounting for the observed saturation of glycopeptide dendrimer galactosyl groups and LecA binding sites is proposed based on the crystal structure of a G3 dendrimer LecA complex.

Commercial Porcine Gastric Mucin Preparations, also Used as Artificial Saliva, are a Rich Source for the Lectin TFF2: In Vitro Binding Studies

“…The latter possibility could eventually be tested in the future by using dendrimer technology. [49] Of special note, the binding of porcine TFF2, which is not glycosylated, was dependento nC a 2 + to some extent (Figure 6B). This feature is typicalo fm any lectins.…”

“…Alternatively, clustering of glycans on the mucin could also enhance TFF2 binding. The latter possibility could eventually be tested in the future by using dendrimer technology …”

Targeting Bacterial Biofilm: A New LecA Multivalent Ligand with Inhibitory Activity

“…The biofilm was analyzed by quantifying the amount of P. aeruginosa PAO1 biofilm formed after 24 h of growth in Muller Hinton medium in polystyrene microtiter plates in the presence or absence of 50 or 250 μ m Gal18, compound 8 , used as blank control, and d ‐galactose . The biofilm was quantified by the crystal violet (CV) assay, measuring the amount of CV bound to biofilm in each well of the microtiter plate, normalized by the optical density of the corresponding culture.…”

Prevention of catheter-related bloodstream infections in patients on hemodialysis: challenges and management strategies

“…15 Independently, bacteria may cause acute infections; collectively, they form sessile slime-enclosed aggregates that are resistant to extermination. The presence of a biofilm is not limited to catheter-related infections; biofilm can be seen in vivo in relation to nonhematogenous organs, such as pneumonia associated with cystic fibrosis 16 as well as contaminated …”