Multivalent carbohydrate inhibitors of bacterial lectins and toxins

Abstract

Bacteria and their toxins often carry proteins on their surface binding to specific components of tissue cells or the extracellular matrix. In many cases the components are carbohydrate structures. The adhesion of these carbohydrate-binding proteins, named lectins, to human glycoconjugates is a prerequisite for the subsequent bacterial infection and disease.Regarding the role of lectins played in infection, selectively blocking of the binding to host cells by taking carbohydrate derivatives represents an effective therapeutic strategy at an early stage. Alarmingly, the emerging crisis of antibiotic resistance emphasizes the need for antibiotics with more effective therapeutic effects. In this PhD research, several studies had been conducted to investigate principal virulence factors e.g. Pseudomonas aeruginosa LecA (PA-IL), Cholera toxin (CT) and Streptococcus suis (S. suis) for public health problems. Numerous studies have identified that the interaction of an individual saccharide unit with a given protein is relatively weak. Indeed, a high level of affinity is required to promote bacterial invasion. A multivalency effect also known as the “glycoside cluster effect” has been a key principle exploited in nature to circumvent the intrinsically low affinity of a single ligand-receptor interaction. Concerning the exceptional oligomeric protein structure of lectins, we were inspired to employ the multivalent approach to design and synthesize multivalent glycomimetics as potential therapeutic agents by linking various sugar units to scaffolds. The multivalent displays of carbohydrates of interest offered various classes of glycoconstructs including glycodendrimers and glycopolymers aiming to interfere with carbohydrate-mediated pathogen adhesion. The evaluation of binding properties of the resulting multivalent carbohydrate ligands were probed by a variety of techniques e.g. ELISA, ITC, SV-AUC assays, etc. In comparison to their corresponding monovalent counterparts. Besides the valencies, other functional elements related to multivalent system presentation also affected their binding performance including the length and functionality of spacer, the optimization of ligand architecture and the spatial arrangement of ligands on multivalent molecules. Their importance had been discussed in this thesis. The current findings highlighted the importance of the multivalency concept in the inhibition of carbohydrate-bacterial (toxin) adhesion and illustrates how it could benefit the inhibitory potency and selectivity of these multivalent glycoconjugates. These advances are crucial, and lead to a better understanding of multivalent recognition events at the molecular level. This work also suggests that the binding properties of multivalent ligands could, thereby, be used for therapeutic intervention of carbohydrate-mediated host-pathogen interactions in general.