Discovery of N-?-L-Fucosyl Amides as High-Affinity Ligands for the Pseudomonas aeruginosa Lectin LecB

nosa causes severe infections mainly in immunocompromised or cystic fibrosis patients and is able to resist antimicrobial treatments. The extracellular lectin LecB plays a key role in bacterial adhesion to the host and biofilm formation. For the inhibition of LecB, we designed and synthesized a set of fucosyl amides, sulfonamides, and thiourea derivatives. Then, we analyzed their binding to LecB in competitive and direct binding assays. We identified beta-fucosyl amides as unprecedented high-affinity ligands in the two-digit nanomolar range. X-ray crystallography of one alpha- and one beta anomer of N-fucosyl amides in complex with LecB revealed the interactions responsible for the high affinity of the beta-anomer at atomic level. Further, the molecules showed good stability in murine and human blood plasma and hepatic metabolism, providing a basis for future development into antibacterial drugs.

Automated summary

This study identified beta-fucosyl amides as high-affinity ligands for LecB, providing a basis for future development into antibacterial drugs.