Pseudomonas aeruginosa (P. aeruginosa) is one of the community-acquired and healthcare-associated infections causing organisms. It has become resistant to most of the available antibiotics and is termed multi-drug resistance (MDR). There are a limited number of antibiotics are available to treat such MDR organism causing infections. The ceftolozane/tazobactam is one among the combination drug therapy (CDT) prescribed for the treatment of MDR causing infections. The resistance for the same CDT was observed in the MDR P. aeruginosa harboring VIM-5 and IMP-7 Metallo beta (β)-lactamases (MBLs). To explore the resistance mechanism at the molecular level, docking studies were carried out for antibiotics against VIM-5 and IMP-7 MBLs. The Zn2 metal ions carry out the nucleophile attack on the carbonyl carbon of the β-lactam ring along with conserved water molecules. To find lead compounds against the MBLs, a virtual screening process was carried out. We have employed MODELLER for structure modeling, AutoDock for molecular docking and AutoDock Vina, Molinspiration, PASS prediction & admetSAR in virtual screening. The search of low binding energy ceftolozane analogs against VIM-5 and IMP-7 MBLs has resulted in the ZINC000029060075 and ZINC000009163636 analogs. Similarly, the screening of high binding energy inhibitors against VIM-5 and IMP-7 MBLs has resulted in ZINC000003831503 and ZINC000000897247 tazobactam analogs respectively. The ADMET prediction results in the non-toxicity of the lead compounds. Our study may provide new insights for the scientist who are designing novel drugs against MDR P. aeruginosa causing infections.

中文翻译：

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了解头孢唑烷/他唑巴坦与铜绿假单胞菌的金属-β-内酰胺酶 VIM-5 和 IMP-7 的结合构象：分子对接和虚拟筛选过程

铜绿假单胞菌( P. aeruginosa )是引起社区获得性和医疗保健相关感染的生物体之一。它已经对大多数可用的抗生素产生抗药性，被称为多药耐药性（MDR）。可用于治疗这种引起感染的 MDR 微生物的抗生素数量有限。头孢唑烷/他唑巴坦是用于治疗引起感染的 MDR 的联合药物治疗 (CDT) 之一。在 MDR P中观察到相同 CDT 的抗性。绿脓杆菌含有 VIM-5 和 IMP-7 金属β (β)-内酰胺酶 (MBL)。为探索分子水平的耐药机制，对抗生素针对VIM-5和IMP-7 MBLs进行了对接研究。Zn2 金属离子与保守的水分子一起对 β-内酰胺环的羰基碳进行亲核试剂攻击。为了找到针对 MBL 的先导化合物，进行了虚拟筛选过程。我们使用 MODELLER 进行结构建模，使用 AutoDock 进行分子对接，使用 AutoDock Vina、Molinspiration、PASS 预测和 admetSAR 进行虚拟筛选。针对 VIM-5 和 IMP-7 MBLs 的低结合能头孢唑烷类似物的研究产生了 ZINC000029060075 和 ZINC000009163636 类似物。相似地，针对 VIM-5 和 IMP-7 MBLs 的高结合能抑制剂的筛选分别产生了 ZINC000003831503 和 ZINC000000897247 他唑巴坦类似物。ADMET 预测导致先导化合物无毒。我们的研究可能为正在设计抗 MDR 新药的科学家提供新的见解磷。引起感染的绿脓杆菌。