Halder Sajal Kumar, Mim Maria Mulla, Alif Md Meharab Hassan, Shathi Jannatul Fardous, Alam Nuhu, Shil Aparna, Himel Mahbubul Kabir
Department of Biochemistry and Molecular Biology, Jahangirnagar University Savar Dhaka 1342 Bangladesh.
Research Assistant at Padma Bioresearch Dhaka Bangladesh.
RSC Adv. 2022 Aug 26;12(37):24319-24338. doi: 10.1039/d2ra02939a. eCollection 2022 Aug 22.
Antimicrobial resistance is a major global health crisis, resulting in thousands of deaths each year. Antibiotics' effectiveness against microorganisms deteriorates over time as multidrug resistance (MDR) develops, which is exacerbated by irregular antibiotic use, poor disease management, and the evasive nature of bacteria. The World Health Organization has recognized multidrug resistance as a critical public health concern, and has been at the center of attention due to its ability to develop multidrug resistance (MDR). It generally produces carbapenem-hydrolyzing oxacillinase, which has been identified as the primary source of beta-lactam resistance in MDR bacteria. Recently, point mutations in have been identified as a key factor of multidrug resistance, making them a prime concern for researchers. The goal of the current work was to establish a unique way of finding multidrug-resistant variants and identify the most damaging mutations in the existing databases. We characterized the deleterious variants of oxacillinases using several computational tools. Following a thorough analysis, Oxa-376 and Oxa-530 were found to be more damaging when compared with the wild-type Oxa-51. The mutants' 3D structures were then prepared and refined with RaptorX, GalaxyRefine, and SAVES servers. Our research incorporates seven antimicrobial agents to illustrate the resistance capability of the variants of oxacillinase by evaluating binding affinity in Autodock-vina and Schrodinger software. RMSD, RMSF, Radius of gyration analysis, the solvent-accessible surface area (SASA), hydrogen bonding analysis and MM-GBSA from Molecular Dynamics Simulation revealed the dynamic nature and stability of wild-type and Oxa-376 and Oxa-530 variants. Our findings will benefit researchers looking for the deleterious mutations of and new therapeutics to combat those variants. However, further studies are necessary to evaluate the mechanism of hydrolyzing activity and antibiotic resistance of these variants.
抗菌药物耐药性是一场重大的全球健康危机，每年导致数千人死亡。随着多药耐药性（MDR）的出现，抗生素对微生物的有效性会随着时间推移而下降，不规范使用抗生素、疾病管理不善以及细菌的逃避特性加剧了这种情况。世界卫生组织已将多药耐药性视为一个关键的公共卫生问题，并且由于其产生多药耐药性的能力而一直备受关注。它通常会产生碳青霉烯水解型奥沙西林酶，该酶已被确定为MDR细菌中β-内酰胺耐药性的主要来源。最近，[此处原文缺失相关基因名称]中的点突变已被确定为多药耐药性的关键因素，这使其成为研究人员的主要关注点。当前工作的目标是建立一种独特的方法来寻找多药耐药变体，并在现有数据库中识别最具破坏性的突变。我们使用多种计算工具对奥沙西林酶的有害变体进行了表征。经过全面分析，发现与野生型Oxa-51相比，Oxa-376和Oxa-530更具破坏性。然后使用RaptorX、GalaxyRefine和SAVES服务器制备并优化了突变体的三维结构。我们的研究纳入了七种抗菌剂，通过在Autodock-vina和Schrodinger软件中评估结合亲和力来阐明奥沙西林酶变体的耐药能力。来自分子动力学模拟的均方根偏差（RMSD）、均方根波动（RMSF）、回转半径分析、溶剂可及表面积（SASA）、氢键分析和MM-GBSA揭示了野生型以及Oxa-376和Oxa-530变体的动态性质和稳定性。我们的研究结果将有助于研究人员寻找[此处原文缺失相关基因名称]的有害突变以及对抗这些变体的新疗法。然而，有必要进一步研究以评估这些变体的水解活性机制和抗生素耐药性。
