Discovery and analysis of two novel β-lactamase inhibitors: In vitro, molecular docking, molecular dynamics simulation, and ADMET analyses

The World Health Organization (WHO) has identified antibiotic resistance as one of the most pressing public health threats of the 21st century and emphasized the critical role of β-lactam antibiotics in the treatment of bacterial infections. However, the efficacy of these antibiotics is severely compromised by β-lactamases enzymes such as extended-spectrum β-lactamases (ESBLs), which are produced by bacteria and hydrolyze the β-lactam ring, rendering the antibiotic ineffective. Therefore, inhibition of β-lactamases is critical to restoring the efficacy of β-lactam antibiotics. In this study, the β-lactamase inhibitor potential of two novel compounds was evaluated against ten β-lactams. Initially, the compounds were characterized using HRMS, FT-IR, ¹H NMR, and ¹³C NMR techniques. Their inhibitory potential was then assessed through molecular docking analysis, and the results were compared with known inhibitors such as clavulanic acid (CA), sulbactam (SB), tazobactam (TZ), avibactam (AV), and ANT43. In vitro validation of novel compounds was carried out on S. aureus ATCC 29213. Consequently, one of the compounds, namely, L2, was evaluated as a potential β-lactamase inhibitor; molecular docking result was confirmed by molecular dynamics simulation, and its toxicity and pharmaceutical properties were further confirmed through ADMET analysis.