Beta-lactamase inhibitors: agents to overcome bacterial resistance

The extensive use of beta-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 -lactamases, which have emerged in both gram-positive and gram-negative bacteria. A novel approach to countering bacterial beta-lactamases is the delivery of a beta-lactam antibiotic in combination with a beta-lactamase inhibitor. Several such combinations are currently available, containing inhibitors clavulanic acid, sulbactam and tazobactam. These inhibitors are not, however, active against all beta-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 beta-lactamase inhibitors. This review offers an overview of synthetic beta-lactamase inhibitors, emphasizing information on their structures, and highlighting their activity against various beta-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.