Crystallographic studies of novel inhibitors of [beta]-lactamases

Bacterial expression of -lactamases is the most widespread resistance mechanism to -lactam antibiotics. There is a pressing need for novel, non- -lactam inhibitors of these enzymes [1]. Our efforts to overcome bacterial resistance mechanisms have been directed towards novel, non -lactam inhibitors of AmpC -lactamase, a class C enzyme responsible of resistance to antibiotics treatment in gram- negative bacteria. Through a structure-based approach, we discover novel inhibitors for this enzyme, with covalent mechanism of action such as boronic acid derivatives and with no-covalent, competitive mechanism of action, such as thiophene-2-carboxylic acid derivative [2]. In one case we were able to extend the inhibitory activity towards class A -lactamases, obtaining a broad spectrum, highly potent inhibitor. Some inhibitors were active in cell culture, reversing resistance to the third generation cephalosporin ceftazidime in bacterial pathogens expressing AmpC and did not up-regulate -lactamase expression in cell culture. The structure-based design, synthesis, biological evaluation and the crystallographic studies of such novel inhibitors will be described. [1] Cosgrove S., Carmeli Y., Clin. Infect. Dis., 2003, 36, 1433-1437. [2] Tondi D., Morandi F., Bonnet R., Costi M. P., Shoichet B. K., J. Am. Chem. Soc., 2005, 127(13), 4632-4639. Keywords: enzyme inhibition, drug resistance, X-ray complexes