The discovery and development of modified penicillin- and cephalosporin-derived β-lactamase inhibitors

While beta-lactam antibiotics remain among the most commonly prescribed pharmaceutical products, their effectiveness is currently threatened by the development of bacterial resistance. One key resistance mechanism is the ability to destroy the antibiotic through utilization of one or more types of beta-lactamase. An effective countermeasure is to employ a combination product, consisting of both a beta-lactam antibiotic and a lactamase inhibitor. Unfortunately, currently available inhibitors narrowly target only class A beta-lactamases. This review will detail our research, directed toward the development of a useful broad-spectrum beta-lactamase inhibitor. In the process, we have discovered new inhibitors capable of simultaneously inactivating class A, C, and D beta-lactamase, produced conjugate siderophore/beta-lactamase inhibitors, and explored the SAR's of tunable, cephalosporin-derived beta-lactamase inactivators. Useful synthetic methodology will be described, which simplifies the large scale production of many known inhibitors and which allows the rapid preparation of libraries of prospective inhibitors.