Targeting bacterial adhesion: Recent advances and therapeutic potential of FimH and PapG inhibitors against Escherichia coli infection.

The widespread use and abuse of antibiotics have led to an increase in antibiotic resistance, and new methods and approaches are needed to combat bacterial infections. One promising alternative is to intervene early stage in the infection process. Adhesion is a prerequisite for bacteria to colonize on the cell surface. Various pathogenic Escherichia coli strains utilize carbohydrate-specific lectins to bind to specific glycoconjugate receptors on host cells for cell adhesion. The most important and best-studied bacterial lectins are FimH and PapG. Therefore, blocking the adhesion of bacteria to cells mediated by FimH and PapG through high-affinity carbohydrate antagonists is an extremely attractive therapeutic target. This paper systematically reviews the research progress of FimH and PapG inhibitors over the past two decades. For FimH-targeted mannoside antagonists, we elaborate the effects of glycosidic linkage types, aromatic substituent modification, conformational rigidification and multivalent structural design on binding affinity, metabolic stability and in vivo performance. Meanwhile, we outline the research framework of high-affinity PapG inhibitors based on galactose scaffolds. Classical optimization strategies, including terminal aromatic group modification, selective hydroxyl substitution and hydrophobic moiety incorporation, can effectively improve the binding affinity and isoform selectivity of PapG ligands. In addition, multivalent modification acts as a universally effective strategy for both FimH and PapG inhibitors. Furthermore, we prospect the rational design directions of anti-adhesive agents in the future, providing systematic theoretical reference and practical guidance for the subsequent structural optimization, pharmacological evaluation and clinical translation of FimH and PapG inhibitors.