Multivalent mannosylated polymer and supramolecular architectures for pathogen inhibition

Abstract

Bacterial adhesion to host tissues is a critical step in the pathogenesis of infections, particularly in the case of urinary tract infections (UTIs), where carbohydrate-lectin interactions mediate pathogen binding. This thesis presents the design, synthesis, and characterization of multivalent mannosylated polymer and supramolecular architectures aimed at inhibiting bacterial adhesion through targeted molecular interactions. The work focuses on dendritic polyglycerol (dPG)-based nanogels (NGs) and supramolecular assemblies as potential therapeutic agents. A series of novel dPG-based macromonomers were synthesized to develop three-dimensional (3D) and two-dimensional (2D) NGs. The synthesis of 3D-NGs demonstrated precise control over size and long-term stability, enabling scalable production while maintaining essential physicochemical properties. Mannosylation of these NGs achieved near-theoretical efficiency, preserving their structural integrity and enhancing their bioactivity in lectin binding studies. The 2D-NGs, synthesized using a graphene template, exhibited well-defined sheet-like architectures with controlled surface chemistry, providing a robust platform for carbohydrate-based recognition systems. The differences in structural organization between 3D- and 2D-NGs directly influenced their binding behaviour, with 2D-NGs demonstrating superior specificity in FimH interactions, while 3D-NGs exhibited enhanced multivalent interactions with ConA. Beyond nanostructured polymeric architectures, this thesis explores supramolecular assemblies of mannosylated amphiphiles in combination with benzene-1,3,5-tricarboxamide (BTA)-based polymers. Novel mannosylated amphiphiles were synthesized and characterized to study their selfassembly and biological interactions. The synthetic strategies included click chemistry and protecting group manipulations for the targeted introduction of mannose motifs. These self-assembled systems were systematically characterized, revealing that alkyl chain length and mannosylation patterns significantly impact aggregation behaviour and bioactivity. While successful co-assembly with BTA fibers was achieved, biological evaluation indicated that supramolecular organization did not always present mannose residues in an optimal conformation for FimH-mediated adhesion-inhibition. The study highlights key structure-activity relationships in carbohydrate-based multivalent interactions, providing insights into the design of nextgeneration anti-adhesive materials. Future directions include optimizing synthetic strategies for enhanced stability, evaluating binding kinetics under physiological conditions, and exploring multiligand functionalization for advanced targeting applications. This research advances the understanding of architecture-dependent bacterial adhesion-inhibition and lays the foundation for developing carbohydrate-based therapeutics against pathogen infections.