The ability to produce one or more b-lactamases represents the most common form of bacterial resistance to the b-lactam antibiotics. One successful method of countering such resistance is the co-administration of a b-lactam antibiotic and a b-lactamase inhibitor. Historically, such combination products have been both efficacious and commercially successful. However, despite the rising clinical incidence of class B (metallo) and classes C and D (serine) b-lactamases, current commercial b-lactamase inhibitors narrowly target the class A (serine) enzymes. Our research group has recently reported efficacious new inhibitors of the serine b-lactamases. These compounds are not only superior to the best commercially available inhibitors of the class A b-lactamases, but are also simultaneously effective against class C and class D enzymes. The current proposal involves a new class compounds, selected example of which have already been synthesized and already proven to be effective inhibitors of both class B metallo-b-lactamases as well as one or more of the serine classes. These compounds were designed by taking advantage of the similar substrate specificity of the metallo and serine-b-lactamases (i.e. the specificity to hydrolyze appropriately substituted bicyclic b-lactams). Thus, these compounds are mechanism based inhibitors of both serine and metallo-b-lactamases and are the first reported penicillin-derived inhibitors of the metallo-b-lactamases. These new inhibitors fill an important scientific and commercial gap, allowing for the first time, potential commercialization of a class B (metallo) b-lactamase inhibitor. Therefore, we now propose the further development of this class of compounds into a viable pharmaceutical product. Synthetic methodology has already been developed to facilitate the preparation of more examples of this class of molecules. A group of scientists, including chemists, microbiologists, enzymologists, and crystallographers has been assembled to allow rapid optimization of SAR.
