Overcoming antibiotic resistance in Pseudomonas aeruginosa biofilms using glycopeptide dendrimers

Abstract

Glycopeptide dendrimers targeting P. aeruginosa lectins yielded to crystallography and acted in synergy with tobramycin for biofilm inhibition and dispersal.

Development of Pseudomonas aeruginosa Lectin LecA Inhibitor by using Bivalent Galactosides Supported on Polyproline Peptide Scaffolds

“…Others have also developed very potent LecA inhibitors through structural modifications and refinements, such as Reymond et al. (glycopeptide dendrimer, 2.5 n m , isothermal titration calorimetry (ITC)), Pieters et al. (rigid dimer, 28 n m , ITC), Imberty, Römer, Winssinger et al.…”

“…The activitieso fo ur glycoconjugates are comparable to the glycodendrimers reported by Roy et al (230 nm,S PR). [21] Others have also developed very potent LecA inhibitors through structural modifications andr efinements, such as Reymond et al (glycopeptide dendrimer,2 .5 nm,i sothermal titration calorimetry (ITC)), [22] Pieterse tal. (rigid dimer,2 8nm,I TC), [34] Imberty, Rçmer,W inssinger et al (glycopeptide dimer,8 2nm,I TC), [38]…”

“…[16] Another approach to enhancei nhibitor interaction to LecA is through multivalent binding. Because LecA is at etrameric lectin andt he two closest binding sites are separated by about 26 , [17] various artificial scaffolds including dendrimers, [11,[18][19][20][21][22][23][24] clusters, [12][13][14][25][26][27][28][29][30][31][32] and linear rigid spacers [33][34][35][36] have been exploited to present galactoside ligands to theb inding sites to enhancei nhibition activity. [37] In other cases, the artificial scaffoldsa re furtherf unctionalized to generate extra interactions with LecA for stronger binding.…”

Antimicrobial Peptide Dendrimer Chimera

“…In the course of investigating peptide dendrimers as enzyme models and for nucleic acids and drug delivery, [14 -18] we discovered compounds acting on bacteria, either in the form of glycopeptide dendrimers targeting lectins and capable of inhibiting biofilms, [19][20][21] or as polycationic dendrimers exerting membrane perturbation effects. We identified our first membrane disrupting antimicrobial peptide dendrimer (AMPD) by screening a combinatorial library using an off-bead Bacillus subtilis growth inhibition assay, [22 -24] which pointed to dendrimer bH1, a third generation (G3) dendrimer containing single hydrophobic residues in its branches and eight positive charges at the N-termini ( Figure 1, Table 1).…”

Covalent Lectin Inhibition and Application in Bacterial Biofilm Imaging

“…[7] Thus,t he inhibition of these lectins provides ap romising way to dismantle the bacterium from the protective biofilm environment and restore immune defense and activity of antibiotics. [8] Current approaches to inhibit both lectins range from small molecules to multivalent structures and are summarized in recent reviews. [9] We focus on the development of small molecules and recently published various potent glycomimetic inhibitors for the high affinity lectin LecB as inhibitors of P. aeruginosa adhesion.…”