β-Lactamases are the main cause of bacterial resistance to penicillins, cephalosporins and related β-lactam compounds. These enzymes inactivate the antibiotics by hydrolysing the amide bond of the β-lactam ring. Class A β-lactamases are the most widespread enzymes and are responsible for numerous failures in the treatment of infectious diseases. The introduction of new β-lactam compounds, which are meant to be ‘β-lactamase-stable’ or β-lactamase inhibitors, is thus continuously challenged either by point mutations in the ubiquitous TEM and SHV plasmid-borne β-lactamase genes or by the acquisition of new genes coding for β-lactamases with different catalytic properties. On the basis of the X-ray crystallography structures of several class A β-lactamases, including that of the clinically relevant TEM-1 enzyme, it has become possible to analyse how particular structural changes in the enzyme structures might modify their catalytic properties. However, despite the many available kinetic, structural and mutagenesis data, the factors explaining the diversity of the specificity profiles of class A β-lactamases and their amazing catalytic efficiency have not been thoroughly elucidated. The detailed understanding of these phenomena constitutes the cornerstone for the design of future generations of antibiotics.

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