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The β-lactam antibiotics are the most effective medicines for treating bacterial infections. Resistance to them, particularly through the production of β-lactamases, which can hydrolyse all kinds of β-lactams, poses a threat to their continued use. The synthesised flavone and coumarin based isoxazole derivatives have the potential to be used as broad-spectrum inhibitors of the mechanistically different serine-(SBL) and metallo-β-lactamases (MBL). The synthesised compounds were discovered as potent β-lactamase inhibitors using molecular docking and  in silico  pharmacokinetic analysis. We studied the binding of chemically synthesised inhibitors to clinically significant β-lactamases of class A, B, and C using biophysical and biochemical approaches, and computational analyses. These molecules follow Lipinski’s rule of five and have acceptable solubility, permeability, and oral bioavailability. These molecules were found to be non-toxic and non-carcinogenic. MIC results suggest that these molecules restore the antibiotic efficacy against class A, B, and C β-lactamases. Kinetics data showed that these molecules reduce the catalytic efficiency of clinically relevant class A, B, and C β-lactamases. Fluorescence study showed significant interaction between these flavone-/coumarin-based isoxazole derivatives and class A/B/ C β-lactamases. This study showed promising effect of these new generation compounds as broad spectrum β-lactamase inhibitors of both SBLs and MBLs. Communicated by Ramaswamy H. Sarma

journal of biomolecular structure and dynamics

Chemically synthesised flavone and coumarin based isoxazole derivatives as broad spectrum inhibitors of serine β-lactamases and metallo-β-lactamases: a computational, biophysical and biochemical study