Non‐Carbohydrate Glycomimetics as Inhibitors of Calcium(II)‐binding Lectins

05 January 2021
Search for new inhibitors of bacterial infection is a priority for fighting antibiotics resistance, and this is the topic of a french-german ANR-DFG project. We screened for libraries of non-carbohydrate ligands for binding to Pseudomonas aeruginosa calcium-dependent lectins, and identified catechol derivatives as interesting lead. The first co‐crystal structure of a non‐carbohydrate inhibitor in complex with a bacterial lectin clearly demonstrates the catechol mimicking the binding of natural glycosides with LecA. Interstingly, catechol derivatives also bind to human C-type lectins, opening a wide range of applications. Click on the title for more information.

Abstract:
« Because of the antimicrobial resistance crisis, lectins are considered novel drug targets. Pseudomonas aeruginosa utilizes LecA and LecB in the infection process. Inhibition of both lectins with carbohydrate‐derived molecules can reduce biofilm formation to restore antimicrobial susceptibility. Here, we focused on non‐carbohydrate inhibitors for LecA to explore new avenues for lectin inhibition. From a screening cascade we obtained one experimentally confirmed hit, a catechol, belonging to the well‐known PAINS compounds. Rigorous analyses validated electron‐deficient catechols as millimolar LecA inhibitors. The first co‐crystal structure of a non‐carbohydrate inhibitor in complex with a bacterial lectin clearly demonstrates the catechol mimicking the binding of natural glycosides with LecA. Importantly, catechol 3 is the first non‐carbohydrate lectin ligand that binds bacterial and mammalian calcium(II)‐binding lectins, giving rise to this fundamentally new class of glycomimetics. »

The article is availaible over here.