β-Lactamase Inhibitors-Clavulanic Acid, Sulbactam and Tazobactam

β-LACTAMASE INHIBITORS—CLAVULANIC ACID, SULBACTAM AND TAZOBACTAM

Expression of β-lactamase enzymes is the most important mechanism through which organisms become resistant to β-lactams. Over 300 different β-lactamase enzymes have been described and they can be classified either by amino acid sequence or by their biochemical properties. The majority of the enzymes have a serine residue at their active site and bear structural and mechanistic similarities to the carboxypeptidases from which they are thought to have evolved. Unlike the transpeptidases and carboxypeptidases, the β-lactamases hydrolyse β-lactam antibiotics very efficiently, releasing fragments of the antibiotics rapidly instead of remaining bound to the ring opened forms for several minutes. A number of successful inhibitors, including clavulanic acid, sulbactam and tazobactam have been developed for use in combination with susceptible β-lactams (amoxicillin, ampicillin and piperacillin, respectively), protecting them from inactivation by the β-lactamases. The inhibitors are hydrolysed by the β-lactamases in the same manner as susceptible β-lactam antibiotics, the β-lactam ring being broken by attack by a serine residue in the active site of the enzyme. Instead of undergoing rapid release from the active site serine, the inhibitors remain bound and undergo one of several different fates. It is thought that the hydrolysed inhibitors can interact with a second enzyme residue in the active site of the β-lactamase, forming a covalently cross-linked, irreversibly inhibited complex. Other categories of β-lactamase enzymes have zinc atoms at their active sites and hydrolyse the β-lactam ring by a different mechanism to the serine based enzymes. These metallo-β-lactamases are not inhibited by clavulanic acid, sulbactam and tazobactam.