Polyvalent Inhibitors of Pseudomonas Aeruginosa Adhesion

We synthesized polymers displaying multiple copies of a peptide from the cystic fibrosis transmembrane conductance regulator (residues 108-117). This peptide is the minimal sequence needed for binding of Pseudomonas aeruginosa. Using an in vitro bacterial internalization assay, our preliminary results indicate that such a polyvalent ligand can prevent P. aeruginosa from attaching to (and being internalized by) epithelial cells. The most effective polymer we synthesized was a polyacrylamide with CFTR peptide covalently attached to 0.5% of its acrylamide subunits. This polymer has an IC50 value of 700 pM, 40,000 times lower than monovalent CFTR peptide. Polyacrylamide at the same concentration does not inhibit internalization. We also developed a simulation to qualitatively describe how a polyvalent ligand binds to a surface. This simulation demonstrates that the polymer binds to the surface cooperatively. Binding can be enhanced by a larger degree of polymerization, a larger fraction of polymer subunits that can attach to the surface, and greater diffusibility of binding sites on the surface.