Dynamic Glycosylated Polymers as Potential Antibacterials – GlycoDyn

WHO has established a list of pathogens (ESKAPE) displaying antimicrobial resistance. Among them, Pseudomonas aeruginosa (PA) is a bacterium involved in multiple infections and is lethal for patients with cystic fibrosis. Bacteria bind to host cells through protein-carbohydrate interactions. Lectins present on the surface of bacteria can be used to target bacteria. Multivalent glycoclusters were designed as inhibitors of PA adhesion by targeting lectins. We demonstrated that these glycoclusters behave as antiadhesive agents against PA pulmonary infection in animal models. GlycoDyn will develop an innovative drug delivery system to efficiently transport antibiotics to PA using a glycosylated polymer conjugated to an antibiotic via a cleavable linker for its release into bacteria. Sugars will be conjugated to the polymer by reversible covalent bonds (acylhydrazones) that will allow to adapt the carbohydrate composition of the polymer to a specific bacterium. This bacterium will select these carbohydrate in situ by a dynamic combinatorial chemistry based on acylhydrazones in equilibrium. The glycosylated polymer will consist of three constitutive entities: (1) a dynamic and reversible part for conjugation to saccharides; (2) a hydrophilic/hydrophobic polymer tail for different formulation strategies (water soluble or nanoparticles) and (3) a cleavable linker carrying the desired antibiotic to ensure its efficient release. The synthesis of non-reversible glycosylated polymers will be carried out for longer-term biomedical applications. The dynamic combinatorial chemistry strategy will allow to rapidly identify the optimal composition of a glycosylated polymer for a given target (lectin or bacteria) and then the non-reversible covalent polymer (e.g. with amide bonds instead of acyl-hydrazones) will be studied for applications in biology.