P. aeruginosa can form biofilms increasing its resilience against antibiotics approximately 1000-fold. Targeting the underlying mechanisms of the biofilm formation or stabilization is an attractive approach for the treatment of P. aeruginosa. Two virulence factors responsible for this process are the lectins LecA and LecB. Their tetrameric structure enables bacterial adhesion to the host cells through cross-linking between bacterial exopolysaccharides. Together with the Titz lab at HIPS Saarbrücken, we have acquired significant knowhow working with these challenging hydrophilic carbohydrate binding sites and generated several new starting points for inhibitors of LecA and LecB (Sommer, 2018; Shanina, 2021; Siebs, 2022). In particular, the identification of non-carbohydrate scaffolds for the replacement of the carbohydrate scaffold (Kuhaudomlarp, 2021) using focused fragment library screening (Shanina, 2022) opened the door for novel chemical matter to be explored overcoming the disadvantages associated with carbohydrate-based glycomimetics as drugs. Alongside conventional fragment libraries, a fragment library derived from the available natural products in the consortium will be used.

LecA/B ligands identified from fragment-based screening will be explored using a SAR-by-catalogue approach. A large panel of highly sensitive biophysical methods such as ligand- and protein-based NMR as well as SPR are available. Insight into protein dynamics and allostery will be gained from protein NMR studies. Cross-validated hits will be evolved into higher affinity compounds through medical chemistry and those with sufficient affinity will be tested in biofilm assays.