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Molecular docking, dynamics and free energy analyses of Acinetobacter baumannii OXA class enzymes with carbapenems investigating their hydrolytic mechanisms.
Journal of Medical Microbiology ( IF 3 ) Pub Date : 2020-08-01 , DOI: 10.1099/jmm.0.001233
Balajee Ramachandran 1 , Jeyaraman Jeyakanthan 1 , Bruno S Lopes 2
Affiliation  

Introduction. Acinetobacter baumannii is a critical priority pathogen listed by the World Health Organization due to increasing levels of resistance to carbapenem classes of antibiotics. It causes wound and other nosocomial infections, which can be life-threatening. Hence, there is an urgent need for the development of new classes of antibiotics. Aim. To study the interaction of carabapenems with class D beta-lactamases (oxacillinases) and analyse drug resistance by studying enzyme–substrate complexes using modelling approaches as a means of establishing correlations with the phenotypic data. Methodology. The three-dimensional structures of carbapenems (doripenem, ertapenem, imipenem and meropenem) were obtained from DrugBank and screened against class D beta-lactamases. Further, the study was extended with their variants. The variants’ structure was homology-modelled using the Schrödinger Prime module (Schrödinger LLC, NY, USA). Results. The first discovered intrinsic beta-lactamase of Acinetobacter baumannii , OXA-51, had a binding energy value of −40.984 kcal mol−1, whereas other OXA-51 variants, such as OXA-64, OXA-110 and OXA-111, have values of −60.638, –66.756 and −67.751 kcal mol−1, respectively. The free energy values of OXA-51 variants produced better results than those of other groups. Conclusions. Imipenem and meropenem showed MIC values of 2 and 8 µg ml−1, respectively against OXA-51 in earlier studies, indicating that these are the most effective drugs for treatment of A. baumannii infection. According to our results, OXA-51 is an active enzyme that shows better interactions and is capable of hydrolyzing carbapenems. When correlating the hydrogen-bonding interaction with MIC values, the predicted results are in good agreement and might provide initial insights into performing similar studies related to OXA variants or other antibiotic–enzyme-based studies.

中文翻译:

鲍曼不动杆菌OXA类酶与碳青霉烯的分子对接,动力学和自由能分析,研究了其水解机理。

介绍。 鲍曼不动杆菌是世界卫生组织列出的至关重要的优先病原体,原因是对碳青霉烯类抗生素的耐药性不断提高。它会导致伤口和其他医院感染,这可能危及生命。因此,迫切需要开发新型的抗生素。目标。要研究碳青霉烯类药物与D类β-内酰胺酶(草酸酰胺酶)的相互作用,并通过使用建模方法研究酶-底物复合物作为建立与表型数据相关性的方法,来分析耐药性。方法。 碳青霉烯类的三维结构(多洛培南,厄他培南,亚胺培南和美洛培南)从DrugBank获得,并针对D类β-内酰胺酶进行了筛选。此外,研究扩展了它们的变体。使用SchrödingerPrime模块(SchrödingerLLC,纽约,美国)对变异体的结构进行同源建模。结果。鲍曼不动杆菌的第一个发现的内在β-内酰胺酶OXA-51的结合能值为-40.984 kcal mol -1,而其他OXA-51变体(例如OXA-64,OXA-110和OXA-111)具有值分别为−60.638,–66.756和−67.751 kcal mol -1。OXA-51变体的自由能值产生了比其他组更好的结果。结论。 亚胺培南和美罗培南在早期研究中对OXA-51的MIC值分别为2和8 µg ml -1,这表明它们是治疗鲍曼不动杆菌感染的最有效药物。根据我们的结果,OXA-51是一种活性酶,显示出更好的相互作用,并且能够水解碳青霉烯。将氢键相互作用与MIC值相关联时,预测结果吻合良好,可能为进行与OXA变体相关的相似研究或其他基于抗生素-酶的研究提供初步见识。
更新日期:2020-08-27
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