PCV - Programme interdiciplinaire en physique et chimie du vivant


Submission summary

The main rationale of this project is to gain information about the recognition process between bacterial lectins and oligosaccharides from a coherent point of view involving chemistry, biophysics, microbiology and structural biology. It also involves kinetic, thermodynamic and structural studies of the supramolecular assemblies of those biological systems. Several glycosylated multivalent ligands have been reported in the literature In order to provide some mimetic tools and probes to tackle this question. We and others, established that the scaffold plays an extremely important role in the presentation of the carbohydrate epitopes for inhibiting specific lectin-carbohydrate interactions. The scaffold could probably modulate the kinetic growth and the size of the lectin-ligand assemblies via supramolecular interactions. Some highly interesting preliminary results are already disclosed in a thesis work from a collaboration between partners 1,2 and 4. By developing bifunctional glycoasterisk ligands having dual properties, marker and ligand at the same time, we propose the concept of dual ligand/sensors with a colored, fluorescent and electrochromic detection. Moreover, this series of ligands are based on persulfurated aromatic cores known to have interesting optoelectronic properties.(15) Preliminary results in hemaaglutination of chicken erythrocyctes provided a near nanomolar inhibition concentration, which is unusual in this field. The variation of several parameters such as carbohydrate units (Partner 4), arm's length, cores and possible branching, will allow us to further modulate the ligand affinity of those glycoasterisks for testing ligand-lectin interactions, multivalency effects, thermodynamic/kinetic parameters, structural biology (Partner 2) and the modulation of some biological activities on bacteria, such as in P. aeruginosa (Partner 3). It is also proposed to create novel sensors based on lectin-carbohydrate interactions. Partner 2 has already characterized the thermodynamics and structure of LecA and LecB interacting with monosaccharides and oligosaccharides (1-5). However, these preliminary studies did not take into account the multivalency of the ligands. Indeed, when presented at the surface of epithetial cells, the oligosaccharides are part of glycoconjugates and are presented as multivalent objects. The use of synthetic ligands prepared by the chemists will allow for new biochemical and biophysical characterization of lectin/ligand interactions. The kinetic parameters of the association will be determined and completed by a structural and a thermodynamical characterization. The biochemical approach will also allow for chosing the highest affinity ligand that will then be used for in vivo experiments by Partner 3 From the microbiological point of view, the project will aim at clearly determining the involvement of P. aeruginosa lectins LecA and LecB in a crucial biological process which is the biofilm formation. Among human pathogenic bacterial species that are found in the environment, P. aeruginosa can form elaborate multicellular structures on surfaces known as biofilms. These bacterial communities facilitate the transmission of pathogens by providing a stable protective environment and by increasing their ability to persist under diverse environmental conditions, rendering them extremely difficult to eradicate. The ability of P. aeruginosa to colonize surfaces is multifactorial and combinatory. This pathogen possesses a unique capability of forming biofilms through a variety of systems combining homo or heteropolymerization of pilin, flagellin or fimbrial subunits into type IVa (6) and type IVb pili (7), flagellum and Cup fimbriae (8, 9) at the bacterial cell surface, secretion of large monomeric adhesive proteins through type I and V secretion systems (10), elaboration of autoproduced exopolysaccharide matrix (EPS) (11-13) and lectins (14). These adhesive systems are expressed in a temporal and synergistic way that remains to be clearly defined during biofilm formation and P. aeruginosa human infections, the implication of LecA and LecB remaining to be clearly defined, especially due to the unclear mechanism by which they can reach the extracellular medium.

Project coordination

Marc GINGRAS (Organisme de recherche)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


Help of the ANR 600,000 euros
Beginning and duration of the scientific project: - 36 Months

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