Tondi Donatella, Cross Simon, Venturelli Alberto, Costi Maria P, Cruciani Gabriele, Spyrakis Francesca
Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 183, 41125, Modena, Italy.
Curr Drug Targets. 2016;17(9):983-1005. doi: 10.2174/1389450116666151001104448.
Nowadays clinical therapy witnesses a challenging bacterial resistance limiting the available armament of antibiotics. Over the decades strains resistant to all antibiotics have been selected while medicinal chemists were not able to develop agents capable of destroying them or to prevent their extension. In particular, carbapenem-resistant Enterobacteriaceae (CRE), representing one of the most common human pathogens, have been reported with increased frequency since their first identification twenty years ago. The enterobacterial carbapenemases differ from the extended spectrum β-lactamases (ESBL) in their ability to hydrolyze β-lactams, cephalosporins and most importantly monobactams and carbapenems. They are progressively spreading throughout the world, therefore leaving no effective β-lactam to cure bacterial infections. Several BLs-carbapenemase Xray structures have been determined making these enzymes attractive targets for structure-based drug design studies. However, very little has been done so far to powerfully address the inhibitor design issues for this emerging type of BLs. Here, we focus on the structural basis for molecular recognition and for broad spectrum activity of class A carbapenemases: based on available 3-dimensional structural information we identify a theoretical pharmacophoric model as a starting point for the development of needed carbapenemases inhibitors.
如今，临床治疗面临着具有挑战性的细菌耐药性问题，这限制了抗生素的可用种类。几十年来，对所有抗生素均耐药的菌株不断出现，而药物化学家却未能研发出能够消灭这些菌株或阻止其传播的药物。特别是，耐碳青霉烯类肠杆菌科细菌（CRE）作为最常见的人类病原体之一，自20年前首次被发现以来，其报告出现频率不断增加。肠杆菌科碳青霉烯酶在水解β-内酰胺类、头孢菌素类，最重要的是单环β-内酰胺类和碳青霉烯类药物的能力方面，与超广谱β-内酰胺酶（ESBL）有所不同。它们正在全球范围内逐渐传播，导致没有有效的β-内酰胺类药物来治疗细菌感染。几种β-内酰胺类-碳青霉烯酶的X射线结构已被确定，这使得这些酶成为基于结构的药物设计研究的有吸引力的靶点。然而，到目前为止，针对这种新型β-内酰胺酶的抑制剂设计问题，所做的工作还非常少。在这里，我们专注于A类碳青霉烯酶分子识别和广谱活性的结构基础：基于现有的三维结构信息，我们确定了一个理论药效团模型，作为开发所需碳青霉烯酶抑制剂的起点。
