Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio 44106, United States.
Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106, United States.
J Med Chem. 2020 Jun 11;63(11):5990-6002. doi: 10.1021/acs.jmedchem.0c00255. Epub 2020 Jun 2.
Treatment of multidrug-resistant Gram-negative bacterial pathogens represents a critical clinical need. Here, we report a novel γ-lactam pyrazolidinone that targets penicillin-binding proteins (PBPs) and incorporates a siderophore moiety to facilitate uptake into the periplasm. The MIC values of γ-lactam YU253434, , are reported along with the finding that is resistant to hydrolysis by all four classes of β-lactamases. The druglike characteristics and mouse PK data are described along with the X-ray crystal structure of binding to its target PBP3.
治疗多重耐药革兰氏阴性菌病原体是一项重要的临床需求。在这里，我们报告了一种新型的γ-内酰胺吡唑烷酮，它靶向青霉素结合蛋白（PBPs）并包含一个铁载体部分，以促进进入周质。报告了γ-内酰胺 YU253434 的 MIC 值，并且发现 对所有四类β-内酰胺酶的水解均具有抗性。描述了药物特征和小鼠 PK 数据，以及与靶标 PBP3 结合的 的 X 射线晶体结构。
