The French National Research Agency Projects for science

Voir cette page en français

ANR funded project

RECHERCHES PARTENARIALES ET INNOVATION BIOMEDICALE (RPIB) 2012
Projet PA-Control

Proof of concept study for new Multivalent Glycomimetics active against Pseudomonas aeruginosa adhesion and biofilm formation

The present project aims at conceiving and synthetizing high affinity multivalent glycomimetics active against Pseudomonas aeruginosa (PA) adhesion and biofilm formation trough competitive inhibition of lectin interactions with host carbohydrates.

The objective of the project is to identify the best PA lectin ligands through the screening of a large library of natural polysaccharides and oligosaccharides (300 compounds-OligoTech®) issued from manufacturable processes (fermentation or controlled extraction) and then, to incorporate these carbohydrates in multivalent macromolecular structures to obtain the best avidity against PA lectins. Glycomimetics are dynamic structures with highly flexible architecture allowing converging to optimal activities.

Thus, the goal of the PA-control is to establish the proof of concept of anti-adhesive activity of high affinity glycomimetics against PA. It opens the field to anti-infectious applications during cystic fibrosis, treatment of nosocomial infections by PA, or water treatment.

PA is a gram negative opportunistic pathogen. It is one of the three most prevalent nosocomial bacterial pathogens (10-30% of nosocomial infections) and is the major cause of morbidity and mortality of cystic fibrosis patient. Colonization of the upper respiratory tract by PA often leads to chronic inflammation and eventually to death despite aggressive antibiotic therapy. Indeed, the emergence of resistant strains and biofilm formation seems to give a selective advantage to the bacterium.
A promising approach is to inhibit the virulence factors of PA and particularly adhesins and lectin involved in the bacterial adhesion or biofilm formation. We have identified 7 PA adhesins or lectins as potential targets: PA-IL, PA-IIL, FliC, FliD, PilA, PilY1 and CupB6. These proteins exploits surface bound carbohydrates of the host such as fucose, galactose, Lex, SLex, Leb.
The literature is well documented with galactosylated or fucosylated glycoclusters (glycomimetics) targeting PA-IL or PA-IIL. However, to our knowledge only very few are targeting the five other lectins.
The main objective of PA-control is the conception and the production of high affinity multivalent glycomimetics targeting these 7 PA adhesins and active against biofilm formation and adhesion. Elicityl is a biotech company based near Grenoble and devoted to complex sugar engineering and production.
Elicityl, the industrial partner of the program, develops an offer of natural polysaccharides and oligosaccharides (OligoTech®) either extracted from biomass or produced by bacterial fermentation (potentially modified thru chemical functionalization).

The inhibitory potential of complex sugar from OligoTech® will be assessed (300 carbohydrates):
• on microarray with over-expresses purified PA-IL, PA-IIL, FliC, FliD, PilA, PilY1 and CupB6,
• selected ligands will then be further evaluated as inhibitor of biofilm formation and adhesion of diverse PA strains on culture cell line, tissue section and human mucins,
• finally, the best ligands will be assembled on a phosphorylated scaffold for enhanced affinity through the cluster effect. The newly synthesized molecules will be evaluated through the two step screening process on microarray followed by in-vitro assays.


This multidisciplinary project combines the complementary know-how of a biotech company with three academic laboratories. It is supported by a knowledge transfer for the industrialization and production of lectins and glycomimetics.

PA-Control will contribute to make available glycomimetics at large scale. This offer would represent an unprecedented offer in the field of glycobiology and glycotechnology and is expected to boost both academic and industrial research in this already rapidly developing area.

Partners

 Elicityl

IBMM Institut des biomolécules Max Mousseron

INL Institut des Nanotechnologies de Lyon

UGSF Laboratoire de Glycobiologie Structurale et Fonctionnelle

ANR grant: 843 425 euros
Beginning and duration: janvier 2013 - 36 mois

 

ANR Programme: RECHERCHES PARTENARIALES ET INNOVATION BIOMEDICALE (RPIB) 2012

Project ID: ANR-12-RPIB-0003

Project coordinator:
Monsieur Benoît DARBLADE (Elicityl)
benoit.darblade@nullelicityl.fr

 

Back to the previous page

 

The project coordinator is the author of this abstract and is therefore responsible for the content of the summary. The ANR disclaims all responsibility in connection with its content.