Chapter 11 : β-Lactam Compounds as β-Lactamase Inhibitors

Abstract:

An understanding of the mechanism of action and the inactivation of native and mutant β-lactamases, together with the identification of positions where amino acid substitutions occurred and the folding properties and flexibility of these enzymes, is important for the design of new effective β-lactam antibiotics as well as inhibitors of these enzymes. Scientists have identified different processes for the inactivation of Escherichia coli TEM-1 (RTEM) β-lactamase by sulbactam. First, sulbactam is a substrate in the sense that the enzyme catalyzes the hydrolytic opening of the β-lactam ring. Second, it is an enzyme inhibitor; at pH 8, about 10 molecules of inhibitor are consumed per enzyme molecule. Thus, interaction of the enzyme with sulbactam gives rise to irreversible inhibition. Clavulanic acid, sulbactam, and tazobactam inhibit exocellular β-lactamases encoded by plasmids from Staphylococcus spp. and group 2 periplasmic β-lactamases (except for some TEM mutants) of gram-negative bacteria. These β-lactamases include the TEM-1 β-lactamase, which is plasmid encoded and is one of the most common β-lactamases found in bacteria. Numerous studies have demonstrated the effectiveness of the clavulanate mixture in primary and recurrent urinary infections caused by susceptible strains of E. coli and other bacteria, including many amoxicillin-resistant strains. It has been used with good results in infections of the skin and soft tissues caused by susceptible pathogens, including β-lactamase-producing strains of Staphylococcus aureus. The broad antibacterial spectrum of piperacillin-tazobactam mixture makes it most useful for the treatment of infections in immunodepressed or neutropenic patients.