耐抗生素鲍曼不动杆菌,铜绿假单胞菌,结核分枝杆菌,金黄色葡萄球菌,肠杆菌感染是严重的全球健康问题,和A类β-内酰胺酶是导致抗生素抗性的一种机制。QPX7728,释放巴坦,和恩美他唑巴坦是新的β-内酰胺酶抑制剂,以对抗β-内酰胺抗性。目前的研究中使用了计算机模拟方法,以发现三种抑制剂中哪一种对所有A类β-内酰胺酶更有效,并揭示了分子对它们结合能之间差异的见解。使用BLDB和ClustalOmega定义β-内酰胺酶活性位点的保守残基中的突变。FastME和MMseq2用于簇和系统发育分析。使用SWISS-MODEL建立了β-内酰胺酶的3D蛋白质结构模型。ERRAT和GalaxyWebServer用于验证42个β-内酰胺酶蛋白结构。QPX7728,释放巴坦,和恩美唑巴坦通过使用AutoDock4.2与β-内酰胺酶对接。TEM76-relebactam,CTX-M-81-relebactam,TEM-76-恩美他唑巴坦,用分子动力学方法对CTX-M-200-恩美他唑巴坦配合物进行了500ns的模拟。根据分子对接结果,relebactam和QPX7728是更有利的丝氨酸Aβ-内酰胺酶抑制剂。配体与β-内酰胺酶之间相互作用的2D表示表明,与TEM-76氢键键合的S235可能在抑制剂设计中起作用。对复合物的500-nsMD分析表明,与S70的距离,酶活性腔中的稳定性,和高原子位移将解释抑制剂结合亲和力的显着差异。
Antibiotic-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, Mycobacterium tuberculosis, Staphylococcus aureus, and Enterobacterales infections are serious global health problems, and class A β-lactamases are one mechanism that leads to antibiotic resistance.
QPX7728, relebactam, and enmetazobactam are new β-lactamase inhibitors to combat β-lactam resistance. in silico approach was used in the current study to find which of the three inhibitors would be more effective for all class A β-lactamases and to reveal molecular insights into the differences between their binding energies. The mutations in conserved residues of the active sites of β-lactamases were defined using BLDB and Clustal Omega. FastME and MMseq2 were used for cluster and phylogeny analysis. 3D protein structure models for β-lactamases were built using SWISS-MODEL. ERRAT and Galaxy Web Server were used to verify 42 β-lactamase protein structures.
QPX7728, relebactam, and enmetazobactam were docked to β-lactamases by using AutoDock 4.2. The TEM76-relebactam, CTX-M-81-relebactam, TEM-76-enmetazobactam, and CTX-M-200-enmetazobactam complexes were simulated by molecular dynamics method for 500 ns. Based on molecular docking results, relebactam and
QPX7728 were more favorable inhibitors for serine A β-lactamases. A 2D representation of the interactions between ligands and β-lactamases showed that S235, hydrogen bonded with TEM-76, might play a role in inhibitor design. A 500-ns MD analysis of complexes indicated that distance from S70, stability in the enzyme active cavity, and high atomic displacement would account for a significant difference in inhibitor binding affinity.