β-Lactamase Inhibitors: Agents to Overcome Bacterial Resistance

The extensive use of β-lactam antibiotics in hospitals and community has created major resistance problems leading to increased morbidity, mortality and health-care costs. Resistance is most often mediated by β-lactamases, which have emerged in both Gram-positive and Gram-negative bacteria. A novel approach to countering bacterial β-lactamases is the delivery of a β-lactam antibiotic in combination with a β-lactamase inhibitor. Several such combinations are currently available, containing inhibitors clavulanic acid, sulbactam and tazobactam. These inhibitors are not, however, active against all β-lactamases and the AmpC chromosomal enzymes that are hyperproduced by some enterobacteria and pseudomonas are a particular 'gap'. Moreover, genes for these AmpC enzymes have begun to escape to plasmids. Consequently, there is a growing need for new broad-spectrum β-lactamase inhibitors. This review offers an overview of synthetic β-lactamase inhibitors, emphasizing information on their structures, and highlighting their activity against various β-lactamases, particularly AmpC enzymes. Effective inhibition of AmpC enzymes are to be found among the penems and monobactams, but none of these has yet proved suitable for pharmaceutical development.