– IN SILICO SCREENING OF NOVEL INHIBITORS OF BETA-LACTAMASES

Bacterial Resistance represents one of the greatest threats to global health leading to a worrying imbalance between bacterial infections, which are becoming more serious and severe, and available treatments gradually getting ineffective. New resistance mechanisms are emerging and spreading worldwide, making infectious diseases very difficult to treat, if not impossible: as a matter of fact, antibiotic resistance is leading us to a pre-antibiotic era. The most prevalent class of antibiotics used in therapy is represented by beta-lactams, while beta-lactamases are versatile enzymes able to hydrolyze and then to inactivate most of available beta lactams antibiotics. To face this risk and overcome resistance, there is a huge need to discover new antibiotics and effective beta-lactamases inhibitors. Our study is focused on the identification of novel inhibitors active against KPC-2 and GES-5, beta - lactamases [1-2] belonging to Class A, and NDM-1 [3-4], from Class B. We used a computational in silico approach: with the computer software Molecular Docking (GLIDE) we performed a virtual screening on a large library of commercially available compounds, previously filtered for drug likeness properties. Our studies led to novel ligands, chemically characterized by several different moiety (i.e carboxylic acids, tetrazoles and pyrrolidines etc). The performed docking studies were supported by preliminary studies on relevant waters mechanistically involved in beta-lactamase enzymes’ hydrolysis mechanism. Flexibility within the active site was also considered for key residues such as Trp105 in KPC-2 and Trp-99 in GES-5. After further docking validation, the molecules selected in silico as most promising inhibitors that have been now directed to in vitro validation.