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.
Highlights
Pseudomonas aeruginosa is an opportunistic Gram negative human pathogen causing lethal airways infections in immunocompromised and cystic fibrosis patients by forming antibiotic resistant biofilms.[1]
We previously reported a single case of a G3 glycopeptide dendrimer by direct SPPS,12c the synthesis was difficult and the isolated yield was very low due to incomplete coupling of the glycosidic end group to the multiple N-termini even with low loading resin (∼0.2 mmol g−1) and large excess of glycosylated reagent
SPPS was first used to prepare a G1 glycopeptide dendrimer featuring the N-terminal dipeptide LysPro of GalAG2 known to engage in direct contact with the lectin, which was acylated at its two N-termini with either 4-carboxyphenyl-β-galactoside to yield GalAG1-Cys or carboxypropyl-β-thiogalactoside to yield GalBG1-Cys
Summary
Pseudomonas aeruginosa is an opportunistic Gram negative human pathogen causing lethal airways infections in immunocompromised and cystic fibrosis patients by forming antibiotic resistant biofilms.[1]. Only very few examples have been reported to interfere with Pseudomonas aeruginosa biofilm formation.[11] In particular we recently reported glycopeptide dendrimers displaying four α-L-C-fucoside groups (FD2: (Fuc-α-CH2CO-LysPro-Leu)4(Lys-Phe-Lys-Ile)2Lys-His-Ile-NH2)[12] or analogs with four galactoside groups (GalAG2: (Gal-β-OC6H4CO-Lys-ProLeu)4(Lys-Phe-Lys-Ile)2Lys-His-Ile-NH2; GalBG2: (Gal-β-S CH2CH2CO-Lys-Pro-Leu)4(Lys-Phe-Lys-Ile)2Lys-His-Ile-NH2)[13] at the end of a common second generation (G2) peptide dendrimer scaffold.[14] These dendrimers bound tightly to their respective lectin, and inhibited the formation and induced partial dispersion of P. aeruginosa biofilms, representing an interesting example of bioactive synthetic dendrimers.[15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
