Antimicrobial resistance is a growing health problem worldwide, requiring new antibacterial agents with innovative mechanisms of action. The principal defensive mechanism developed in the bacterial family involves the inactivation of �-lactam antibiotics by �-lactamases. Therefore, administrating �-lactamases inhibitors with �-lactam antibiotics is an effective approach against antibiotic-resistant bacteria. Moreover, a new class of non-covalent and non-�-lactam inhibitors targeting AmpC �-lactamases is of particular importance for developing new antimicrobial therapies.  In this work, X-ray structures of AmpC �-lactamase were validated for structure-based drug design using self- and cross-docking predictions with the Internal Coordinate Mechanics (ICM) method. Pocket representations with minimal preparation were used as provided in the PDB, whereas refined models were optimized accounting for induced fit movements upon ligand binding. The models were benchmarked for virtual ligand screening purposes. These results provide important insights to the structure-based design of innovative anti-bacterial agents.

Structure-based validation of AmpC β-lactamase for the design of non-covalent inhibitors

243rd National Meeting (2012)

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