Dual Purpose b-Lactamase Inhibitors

描述(申请人提供)：产生一种或多种β-内酰胺酶的能力是细菌对β-内酰胺类抗生素最常见的耐药性形式。对抗这种耐药性的一种成功方法是联合使用β-内酰胺类抗生素和β-内酰胺酶抑制剂。从历史上看，这种组合产品既有效，又在商业上成功。然而，尽管B类(金属)和C类和D类(丝氨酸)β-内酰胺酶的临床发病率不断上升，但目前商业化的β-内酰胺酶抑制剂仅针对A类(丝氨酸)酶。我们的研究小组最近报道了一种有效的新的丝氨酸β-内酰胺酶抑制剂。这些化合物不仅优于商业上最好的A类b-内酰胺酶抑制剂，而且同时对C类和D类酶有效。目前的建议涉及一类新的化合物，其选定的例子已经被合成，并且已经被证明是B类金属-b-内酰胺酶以及一个或多个丝氨酸类的有效抑制剂。这些化合物的设计利用了金属和丝氨酸-b-内酰胺酶相似的底物专一性(即对适当取代的双环b-内酰胺类抗生素的专一性)。因此，这些化合物是丝氨酸酶和金属-β-内酰胺酶的基于机理的抑制剂，是首次报道的青霉素衍生的金属-β-内酰胺酶抑制剂。这些新的抑制剂填补了一项重要的科学和商业空白，首次实现了B类(金属)β-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。合成方法学已经被开发出来，以便于制备更多这类分子的例子。包括化学家、微生物学家、酶学家和结晶学家在内的一群科学家已经聚集在一起，可以快速优化合成孔径雷达。

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.