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The Discovery and Development of Modified Penicillin- and Cephalosporin- Derived β-Lactamase Inhibitors

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While β-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 β-lactamase. An effective countermeasure is to employ a combination product, consisting of both a β-lactam antibiotic and a β- lactamase inhibitor. Unfortunately, currently available inhibitors narrowly target only class A β-lactamases. This review will detail our research, directed toward the development of a useful broad-spectrum β-lactamase inhibitor. In the process, we have discovered new inhibitors capable of simultaneously inactivating class A, C, and D β-lactamase, produced conjugate siderophore / β-lactamase inhibitors, and explored the SAR's of tunable, cephalosporin-derived β-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.
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Keywords: Cephalosporin; lactamase; lactamase inhibitor; siderophore

Document Type: Review Article

Affiliations: Southern Methodist University, Dept. of Chemistry, Dallas, TX 75275-0314, USA

Publication date: 2004-07-01

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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