肺炎克雷伯碳青霉烯酶与β-内酰胺酶抑制蛋白复合物的运动模式

Motion pattern of the complex involved in klebsiella pneumoniae carbapenemases and β-Lactamase inhibitor protein

摘要:

肺炎克雷伯碳青霉烯酶能水解临床治疗多药耐药菌感染的碳青霉烯类抗生素，严重削弱了革兰氏阴性菌感染的治疗效果。开发新型有效专一的肺炎克雷伯碳青霉烯酶酶抑制剂有助于提高此类抗生素的治疗有效率。β-内酰胺酶抑制蛋白能竞争性抑制剂肺炎克雷伯碳青霉烯酶的活性。用粗粒化模型分析了肺炎克雷伯碳青霉烯酶-关键词β-内酰胺酶抑制蛋白复合物的运动模式。结果表明，结合了β-内酰胺酶抑制蛋白后，肺炎克雷伯碳青霉烯酶的运动模式有较大变化。最后用分子对接和分子动力学模拟方法给出了一系列环硼酸类β-内酰胺酶抑制剂与肺炎克雷伯碳青霉烯酶的结合模式，并从氢键和能量的角度解释了该类抑制剂的识别机制与构象-抑制活性间的关系。本研究为后续基于肺炎克雷伯碳青霉烯酶结构的抑制剂设计提供了一定的理论依据。

Abstract:

Carbapenems, used in clinical treatment of multi-drug resistance bacterial infection, can be hydrolyzed by Klebsiella pneumoniae carbapenemases, which weaken the treatment effect of gram negative bacterial infection. It’s an important means of improving the clinical efficiency of these antibiotics to develop novel, potent and specific Klebsiella pneumoniae carbapenemase inhibitors. And β-lactamase inhibitor protein can competitively inhibits Klebsiella pneumoniae carbapenemases. The movement patterns of complex involved in Klebsiella pneumoniae carbapenemase and β-lactamase inhibitor protein are analyzed by coarse-grained models. The results indicate the movement patterns of Klebsiella pneumoniae carbapenemase change a lot after it is inhibited by β-lactamase inhibitor protein. Finally, the binding modes between the series of cyclic boronic acid β-lactamase inhibitors and Klebsiella pneumoniae carbapenemase are released by molecular docking and molecular dynamics simulation, and explained the relationship between the recognition mechanism and conformation-inhibition activity of these inhibitors from the angle of hydrogen bonds and energy. This research provides a theoretical basis of the subsequent design of the inhibitor based on the Klebsiella pneumoniae carbapenemase structure.