β-lactams are one of the most common antimicrobials used to treat bacterial infections. However, bacterial resistance has compromised their efficacy, mainly due to the β-lactamase enzyme production. To overcome this resistance, β-lactamase inhibitors can be used in association with these antimicrobials. Herein, we analyzed the structural characteristics of β-lactamases and their interactions with classical inhibitors, such as clavulanic acid (CA), sulbactam (SB) and tazobactam (TZ) to gain insights into resistance. The homology models of five class A β-lactamases, namely CARB-3, IMI-1, SFO-1, SHV-5 and TEM-10, were constructed and validated and revealed an overall 3D structural conservation, but with significant differences in the electrostatic potential maps, especially at important regions in the catalytic site. Molecular dockings of CA, SB and TZ with these enzymes revealed a covalent bond with the S70 in all complexes, except Carb-3 which is in agreement with experimental data reported so far. This is likely related to the less voluminous active site of Carb-3 model. Although few specific contacts were observed in the β-lactamase-inhibitor complexes, all compounds interacted with the residues in positions 73, 130, 132, 236 and 237. Therefore, this study provides new perspectives for the design of innovative compounds with broad-spectrum inhibitory profiles against β-lactamases.
Keywords: Antimicrobial; Enzyme inhibitor; Molecular modeling; Resistance; β-lactamase.
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