Lectins in the sweet strategy of lung pathogens: from structural glycobiology to design of glycomimetic pathoblockers

Glycan epitopes exposed on the host cell surface serve as receptors for a wide range of proteins expressed by microorganisms. Among these, lectins that are produced by viruses, bacteria, and fungi in either soluble or surface-attached forms, play key roles in infection processes. The fine specificity that many of these glycan-binding proteins display toward human glycan epitopes is the result of long-term co-evolution. Structural insights into lectin architecture, their binding sites, and the atomic details of their interactions with glycans are crucial for designing antimicrobial agents capable of competing with infectious processes and potentially supplementing antibiotics in the current fight against antimicrobial resistance. This review highlights how structural lectinology can serve as a starting point for fruitful collaborations with synthetic carbohydrate chemists in the design, synthesis, and characterization of glycomimetics acting as pathoblockers. Various strategies have been developed to target lectins, exemplified here by soluble lectins from the lung pathogens Pseudomonas aeruginosa and members of the Burkholderia cepacia complex. The affinity for monosaccharide ligands has been enhanced through heterocyclic functionalization using classical medicinal chemistry approaches, with the best results obtained by mimicking natural glycan receptors. Alternatively, the oligomeric nature of lectins allows the design of divalent or multivalent ligands, which exhibit much stronger affinity due to the cluster effect. Covalent inhibitors and non-carbohydrate glycomimetics also represent promising leads for future strategies to combat antimicrobial resistance.