Dual Purpose b-Lactamase Inhibitors

性状（由申请方提供）：产生一种或多种b-内酰胺酶的能力代表了细菌对b-内酰胺抗生素耐药性的最常见形式。对抗这种耐药性的一种成功方法是共同施用b-内酰胺抗生素和b-内酰胺酶抑制剂。历史上，此类组合产品既有效又在商业上成功。然而，尽管B类（金属）和C类和D类（丝氨酸）b-内酰胺酶的临床发病率上升，但目前商业化的b-内酰胺酶抑制剂狭窄地靶向A类（丝氨酸）酶。我们的研究小组最近报道了丝氨酸β-内酰胺酶的有效的新抑制剂。这些化合物不仅上级于市售的A类β-内酰胺酶的最佳抑制剂，而且对C类和D类酶同时有效。目前的建议涉及一类新的化合物，其选择的实例已经合成并已经证明是B类金属-B-内酰胺酶以及一种或多种丝氨酸类的有效抑制剂。通过利用金属和丝氨酸-b-内酰胺酶的相似底物特异性（即水解适当取代的双环b-内酰胺的特异性）来设计这些化合物。因此，这些化合物是丝氨酸和金属-b-内酰胺酶的基于机制的抑制剂，并且是首次报道的青霉素衍生的金属-b-内酰胺酶抑制剂。这些新的抑制剂填补了一个重要的科学和商业空白，首次允许B类（金属）b-内酰胺酶抑制剂的潜在商业化。因此，我们现在建议将这类化合物进一步开发为可行的药物产品。已经开发了合成方法以便于制备更多这类分子的实例。一组科学家，包括化学家，微生物学家，酶学家和晶体学家已经聚集在一起，以允许快速优化SAR。

DESCRIPTION (provided by applicant): 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.