TEM- and SHV-derived extended-spectrum beta-lactamases: relationship between selection, structure and function

The later-generation cephalosporins were developed to overcome beta-lactamases which conferred resistance to earlier beta-lactam drugs. Within two years of their clinical introduction, the ubiquitous TEM and SHV plasmid-encoded beta-lactamase genes underwent simple point mutations that changed key amino acids around the active site of the protein and enabled the enzyme to bind and hydrolyse these new drugs. Successive mutations interacted in concert, radically increasing the enzymes' abilities to bind and confer resistance to later-generation cephalosporins. These modified enzymes have been classified in three groups, based on activity, and altered functions have been correlated with changes in the enzyme structure.