β-Lactam Potentiating Activity, Molecular Docking, and ADMET Analysis of 3-Substituted Coumarins

Drug resistance is a pivotal issue in the treatment of bacterial infections. Thus, discovering alternative drugs is necessary to control antibiotic-resistant bacteria, such as β-lactamase-producing Staphylococcus aureus. Coumarins with C-3 modifications have different inhibitory effects on bacteria, including resistant ones. Here, we evaluate the in vitro and in silico potential of 3-substituted coumarins in inhibiting S. aureus β-lactamase. This study involved assays of antibacterial activity and association with ampicillin to control strains producing β-lactamase, studies of molecular docking with the blaZ-encoded β-lactamase, and analysis of absorption, distribution, metabolism, excretion, and toxicity (ADMET) of 3-substituted coumarins. The derivatives did not inhibit bacterial growth. However, they enhanced the ampicillin activity, reducing the inhibitory concentration by up to 93.75%. Molecular docking revealed the affinity of the compounds to the β-lactamase model and showed that coumarins interact with crucial amino acids for enzymatic activity, such as the Ser70 residue. The ADMET profiles showed favorable predictions and limitations of the derivatives, such as the distribution and higher number of toxicity alerts for coumarins C2 and C3. Therefore, our study highlights the ability of 3-substituted coumarins to inhibit S. aureus β-lactamase and the contribution of C-3 substituents to the resistance modulation and ADMET profile.