Glycopeptide Dendrimers and RAFT's as Antibacterial Agents

• Research unit: COST
• Project number: C06.0012

Key words (English)

peptides; carbohydrates; dendrimers; antibacterial agents; combinatorial chemistry; lectins

Research programs (English)

COST-Action D34 - Molecular targeting and drug design in neurological and bacterial diseases

Short description (English)

This proposal aims at the discovery of high-affinity multivalent glycopeptide dendrimers and RAFTs against bacterial lectins as antibacterial agents which do not trigger bacterial resistance. Multivalent lectin binding inhibits attachment of the bacterium to its host cell and may block infection as shown by the group of Jaeger. This group will deliver purified lectins and also test dendrimer libraries for their effects to inhibit biofilm formation by Pseudomonas aeruginosa. Glycopeptide dendrimer libraries displaying four or eight copies of a carbohydrate grafted on the variable dendritic peptide backbone will be prepared on solid support. The mono-and disaccharide building blocks will be synthesized by the group of Nativi, and the peptide dendrimer libraries will be assembled by the group of Reymond. High-affinity ligands to bacterial lectins will be identified by directed affinity screening of dendrimers libraries using labeled lectins and bacterial toxins. The glycopeptide ligands thus identified will be resynthesized and tested for biological activity by the group of Bonnet. The strategy will be applied to controlling opportunistic pathogens, in particular Pseudomonas aeruginosa, isolated asantibiotic-resistant strains in a hospital environment, in particular beta-lactam resistan strains. The anti-infective glycopeptide dendrimers will be compared and tested as a combination with treatment using quorum sensing inhibitors in the group of Nielsen. The glycopeptide dendrimer libraries will also be used to select for toxin-neutralizing dendrimers, which might be used to prevent host-cell toxicity induced by these toxins. A parallel approach based on rationally designed glycopeptide RAFT will also be identified similar ligands.

Further information (English)

Full name of research-institution/enterprise: Universität Bern Departement für Chemie und Biochemie

Partners and International Organizations (English)

AT, BE, CH, CZ, DE, ES, FR, GR, IE, IL, IT, LT, LV, NL, NO, PL, PT, SI, SK, UK

Abstract (English)

This proposal aimed at the discovery of high-affinity multivalent glycopeptide dendrimers and RAFTs against bacterial lectins as antibacterial agents which do not trigger bacterial resistance, with particular emphasis on the fucose-specific lectin PA-IIL from the opportunistic pathogen Pseudo-monas aeruginosa, which causes lethal respiratory tract infections in cystic fibrosis patients. The projects combines expertise in organic synthesis (Nativi, Firenze, Italy), cyclic peptides (Renaudet, Grenoble, France), dendrimers (Reymond, Berne, Switzerland), microbiology (Jäger, Düsseldorf, Germany), medicinal chemistry (Nielsen, Copenhagen, Denmark) and clinical chemistry (Bonnet, Clermont-Ferrand, France). The project has lead to an intense collaboration between the groups of Grenoble, Düsseldorf and Berne, and lead to several common publications.

References in databases (English)

Swiss Database: COST-DB of the State Secretariat for Education and Research Hallwylstrasse 4 CH-3003 Berne, Switzerland Tel. [phone] Swiss Project-Number: C06.0012