Druggable allosteric sites in β-propeller lectins.

Carbohydrate-binding proteins (lectins) are auspicious targets in drug discovery to combat antimicrobial resistance; however, its non-carbohydrate drug-like inhibitors are still spacious. Here, we present a druggable pocket in a β-propeller lectin BambL from  Burkholderia ambifaria  as a potential target for allosteric inhibitors. This site was identified employing  19 F NMR fragment screening and a computational pocket prediction algorithm SiteMap. The structure-activity relationship study revealed the most promising fragment with a dissociation constant of 0.3±0.1 mM and a ligand efficiency of 0.3 kcal mol -1 HA -1  that affected the orthosteric site. This effect was substantiated by site-directed mutagenesis in the orthosteric and secondary pockets. Future drug-discovery campaigns that aim to develop small molecule inhibitors can benefit from allosteric sites in lectins as a new therapeutic approach against antibiotic-resistant pathogens.