Singh Shubhi, Selvakumar Sahithya, Swaminathan Priya
Department of Biotechnology, School of Bioengineering, College of Engineering and Technology, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, Tamil Nadu, 603203, India.
Mol Divers. 2024 Dec 20. doi: 10.1007/s11030-024-11077-3.
The twenty-first century presents a serious threat to public health due to the growth in antibiotic resistance among opportunistic bacteria, particularly within the ESKAPE group, which includes Enterobacter species with high morbidity, mortality, virulence, and nosocomial dissemination rates. Enterobacter species, especially Enterobacter cloacae, bacteria have developed resistance to multiple antibiotics through mechanisms, such as continuous production of AmpC beta-lactamase. In this study, a comprehensive bioinformatics approach was employed to analyze the genome of Enterobacter cloacae, utilizing sequence data from GenBank (ID: OW968328.1). The AbritAMR and ResFinder tools were utilized to identify antibiotic-resistant genes, which included the presence of blaOXA-48, blaCMH, FosA, OqxA, and OqxB each conferring resistance to specific antibiotics such as β-lactams and fluoroquinolones. These proteins were analyzed using bioinformatics tools such as ProtParam, SOPMA, Robetta, I-TASSER, AlphaFold, and PROCHECK to investigate different structural models and their properties. The models from AlphaFold had the best quality in terms of structural accuracy, providing valuable insights into the 3D conformations of these resistant proteins. Based on the Molecular docking studies, these constructed targets were docked with 20 natural compounds known for their activity against Gram-negative bacteria. Among them, Deacetylnomilin showed the highest docking score and passed their ADMET properties. Molecular dynamic (MD) simulation was conducted for 100 ns for Deacetylnomilin with different resistant proteins. Deacetylnomilin exhibited more favorable binding free energies compared to the reference compounds across all five proteins, indicating higher stability and affinity. These results suggest that Deacetylnomilin could be an effective inhibitor against the resistant proteins of Enterobacter cloacae, making it a promising candidate for further drug development.
由于机会性细菌中抗生素耐药性的增加，21世纪对公共卫生构成了严重威胁，尤其是在ESKAPE组中，该组包括发病率、死亡率、毒力和医院传播率都很高的肠杆菌属物种。肠杆菌属物种，特别是阴沟肠杆菌，已经通过持续产生AmpCβ-内酰胺酶等机制对多种抗生素产生了耐药性。在本研究中，采用了一种全面的生物信息学方法，利用来自GenBank（ID：OW968328.1）的序列数据对阴沟肠杆菌的基因组进行分析。利用AbritAMR和ResFinder工具鉴定抗生素耐药基因，其中包括blaOXA-48、blaCMH、FosA、OqxA和OqxB的存在，它们各自赋予对特定抗生素如β-内酰胺类和氟喹诺酮类的耐药性。使用ProtParam、SOPMA、Robetta、I-TASSER、AlphaFold和PROCHECK等生物信息学工具对这些蛋白质进行分析，以研究不同的结构模型及其特性。就结构准确性而言，AlphaFold的模型质量最佳，为这些耐药蛋白的三维构象提供了有价值的见解。基于分子对接研究，将这些构建的靶点与20种已知对革兰氏阴性菌有活性的天然化合物进行对接。其中，去乙酰诺米林显示出最高的对接分数，并通过了其ADMET性质。对去乙酰诺米林与不同耐药蛋白进行了100纳秒的分子动力学（MD）模拟。与所有五种蛋白质的参考化合物相比，去乙酰诺米林表现出更有利的结合自由能，表明其具有更高的稳定性和亲和力。这些结果表明，去乙酰诺米林可能是阴沟肠杆菌耐药蛋白的有效抑制剂，使其成为进一步药物开发的有前途的候选物。
