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Etudes des adhésines et des lectines flagellaires de Pseudomonas aeruginosa pour le développement de composés antiadhésion. – PA-antiadh

Submission summary

Sugar-protein interactions play an essential role in many cellular processes such as the recognition by the immune system of pathogens. Oligosaccharide-mediated recognition and adhesion are key points in the early steps of bacterial infection. The lectins are specialized carbohydrate-binding proteins involved in host recognition and surface adhesion. They encompass soluble lectins, lectins associated to adhesives organelles such as pili (fimbrial lectins or adhesins) or flagella (flagellar lectins). Blocking their interactions by glycomimetics inhibitors would be a way to fight against bacterial infection but this requires detailed information on the structure, specificity and affinity of the proteins involved. Infections from the opportunist pathogen Pseudomonas aeruginosa often represent a life-threatening event in immuno-compromised patients. It is responsible for numerous nosocomial infections and chronic lung colonization by the bacterium is the major cause of mortality in cystic fibrosis (CF) patients. P. aeruginosa is able to biofilms where it can withstand host immune responses. This adaptive change of the bacterium makes its eradication very difficult since when embedded in biofilm, the bacteria exhibits a dramatically increased resistance to antibiotics and favors persistent and chronic infections. Pseudomonas aeruginosa produces a wide variety of carbohydrate-binding proteins but their role in recognition and adhesion is far from being elucidated. The aim of the work is therefore to identify the functional role and molecular basis of bacteria protein-host sugar specificity for adhesins and flagellar lectins of P. aeruginosa via the combination of complementary approaches: cloning, expression and purification, determination of their specificity and affinity, structural characterization by X-ray crystallography and search for high affinity binding inhibitors. Glycan biosynthetic pathways in bacteria are also attractive therapeutic targets as many of these glycans are associated with cell-surface virulence factors and are unique to prokaryotes. Type b flagellin O-glycosylation, recently described, seems to have a role in the virulence of the bacterium and little information are available on the process. Characterization of the glycosylation clusters composed of 4 genes by structural biology is proposed for a better understanding of the glycosylation mechanism. Our final goal is to design potent inhibitors to limit both the adhesion on inert or mucosal surfaces and the formation of biofilms, which are highly resistant to classical antibiotic therapy. The present study would have potential pharmaceutical application since these inhibitors would be the basis for local anti-adhesion therapy.

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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.

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