通过A类β-内酰胺酶解码碳青霉烯类水解作用的结构基础：对接一个药效团

Title:Decoding the Structural Basis For Carbapenem Hydrolysis By Class A β-lactamases: Fishing For A Pharmacophore

Volume: 17 Issue: 9

Author(s): Donatella Tondi, Simon Cross, Alberto Venturelli, Maria P. Costi, Gabriele Cruciani, Francesca Spyrakis

Affiliation:

关键词: 碳青霉烯酶；圭亚那超广谱β-内酰胺酶（GES）；肺炎克雷伯菌酶（KPC）；非金属碳青霉烯酶（NMC）；药效团预测；粘质沙雷氏菌（SME）；居泉沙雷菌（sfc1）；分子间的相互作用（MIFS）

摘要: 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.

Cite this article as:

Donatella Tondi, Simon Cross, Alberto Venturelli, Maria P. Costi, Gabriele Cruciani, Francesca Spyrakis , Decoding the Structural Basis For Carbapenem Hydrolysis By Class A β-lactamases: Fishing For A Pharmacophore, Current Drug Targets 2016; 17 (9) . https://dx.doi.org/10.2174/1389450116666151001104448