Novel Glycomimetic Ligands for Bacterial Lectins: Design, Synthesis and Biophysical Evaluation

Over the years, antibacterial drug resistance has been recognized as an increasing problem for public health all over the world. Multi-drug resistant (MDR) bacteria emerged to be associated with severe nosocomial infections, representing a serious complication in the hospital settings. Burkholderia cenocepacia is an opportunistic Gram-negative bacterium, which causes infections in immuno-compromised individuals, mainly in cystic fibrosis patients. Several MDR B. cenocepacia strains were found to be insensitive to many classes of antibiotics, making the treatment of related diseases very difficult.1 The establishment of an infection by B. cenocepacia requires adhesion to host cells through carbohydrate/protein interactions. The lectins BC2L, sugar-binding proteins, mediate this process, representing potential targets for the antimicrobial therapy. Indeed, the inhibition of these interactions could prevent microbial adhesion and hinder the infective process. BC2L-C presents an N-terminal trimeric domain, which demonstrates a fucose-binding activity and a C-terminal domain, which recognises mannose.2 This work aims at developing novel fucose-based glycomimetics able to interfere with the carbohydrate–lectin recognition of BC2L-C. A modular fragment-based library of C- and N-glycomimetics has been designed and synthesized, starting from a virtual screening of a fragment library.3 The synthesized compounds were tested for their affinity towards BC2L-C N-terminal domain through different biophysical techniques, including saturation transfer difference NMR spectroscopy (STD-NMR) and isothermal titration calorimetry (ITC). This study allowed to identify hit compounds with increased affinity compared to the monosaccharide parent structure, up to one order of magnitude.4 Starting from a preliminary structure-activity relationships (SAR), a second generation of new ligands has been developed.