Exploring Additional Dimensions of Complexity in Inhibitor Design for Serine β-Lactamases: Mechanistic and Intra- and Inter-molecular Chemistry Approaches.

As a bacterial resistance strategy, serine β-lactamases have evolved from cell wall synthesizing enzymes known as penicillin-binding proteins (PBP), by not only covalently binding β-lactam antibiotics but, also acquiring mechanisms of deacylating these antibiotics. This critical deacylation step leads to release of hydrolyzed and inactivated β-lactams, thereby providing resistance for the bacteria against these antibiotics targeting the cell wall. To combat β-lactamase-mediated antibiotic resistance, numerous β-lactamase inhibitors were developed that utilize various strategies to inactivate the β-lactamase. Most of these compounds are "mechanism-based" inhibitors that in some manner mimic the β-lactam substrate, having a carbonyl moiety and a negatively charged carboxyl or sulfate group. These compounds form a covalent adduct with the catalytic serine via an initial acylation step. To increase the life-time of the inhibitory covalent adduct intermediates, a remarkable array of different strategies was employed to improve inhibition potency. Such approaches include post-acylation intra- and intermolecular chemical rearrangements as well as affecting the deacylation water. These approaches transform the inhibitor design process from a 3-dimensional problem (i.e., XYZ coordinates) to one with additional dimensions of complexity as the reaction coordinate and time spent at each chemical state need to be taken into consideration. This review highlights the mechanistic intricacies of the design efforts of the β-lactamase inhibitors which so far have resulted in the development of "two generations" and 5 clinically available inhibitors.