Balaji Priyanka, N Madhana Priya, Bhaskar M Emmanuel, R Gnanasambandan, Paul Solomon F D, R Magesh
Department of Human Genetics, Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India.
Department of Biotechnology, Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India.
PLoS One. 2025 Feb 18;20(2):e0317941. doi: 10.1371/journal.pone.0317941. eCollection 2025.
Urinary tract infections caused by uropathogenic Escherichia coli (E. coli) are a global health concern, with rising rates and antibiotic resistance demanding novel treatments. Therefore, in this study, we explored the potential of Oxacyclohexadecan-2-one obtained from Moringa oleifera (M. oleifera) seed, as antibacterial agent against three majorly prevalent carbapenemase-producing E. coli proteins, blaNDM-1 (New Delhi metallo-betalactamase-1), blaNDM-5 (New Delhi metallo-betalactamase-5) and blaOXA-48 (Oxacillinase-48) from the strains Ecw3, EC-114 and T20 respectively. The ethanolic extract of M. oleifera seed was subjected to GC-MS, identifying 135 compounds. PyRx virtual screening, identified the top 10 ligands for each protein following the Rule of 5 and ProTox classes V and VI, with Oxacyclohexadecan-2-one (PubChem ID: 235414) showing best binding affinity across all 3 proteins with an optimized dose (LD50) of 5000mg/kg. Hence, molecular docking was carried out for ligand 235414 along with Imipenem, belonging to the same class V toxicity class with an optimized dose (LD50) of 5000mg/kg. Imipenem is a commonly used FDA drug to treat UTIs, which served as the control in the study. Oxacyclohexadecan-2-one showed higher binding affinity for the beta-lactamase proteins with a docking score of -6.45 kcal/mol, -6.05 kcal/mol and -7.34 kcal/mol compared to -3.41 kcal/mol, -3.99 kcal/mol and -6.36 kcal/mol of Imipenem for NDM-1, NDM-5 and OXA-48 respectively. Dynamic Simulation was performed for 100 ns for Oxacyclohexadecan-2-one and Imipenem bound protein complexes to determine the stability, fluctuations, compactness, bond interaction, solvent accessibility area, free energy landscape and the binding free energy. The results of molecular docking and dynamics were promising for the Oxacyclohexadecan-2-one, suggesting its potent inhibitory effect against the beta-lactamase producing proteins.
由尿路致病性大肠杆菌（E. coli）引起的尿路感染是一个全球性的健康问题，发病率不断上升且抗生素耐药性日益严重，急需新的治疗方法。因此，在本研究中，我们探索了从辣木（Moringa oleifera）种子中提取的氧杂环十六烷 - 2 - 酮作为抗菌剂，对分别来自Ecw3、EC - 114和T20菌株的三种主要流行的产碳青霉烯酶大肠杆菌蛋白blaNDM - 1（新德里金属β - 内酰胺酶 - 1）、blaNDM - 5（新德里金属β - 内酰胺酶 - 5）和blaOXA - 48（苯唑西林酶 - 48）的抗菌潜力。辣木种子的乙醇提取物经过气相色谱 - 质谱联用（GC - MS）分析，鉴定出135种化合物。通过PyRx虚拟筛选，依据“五规则”以及ProTox分类V和VI，确定了每种蛋白的前10个配体，其中氧杂环十六烷 - 2 - 酮（PubChem ID：235414）在所有3种蛋白中显示出最佳结合亲和力，优化剂量（半数致死量，LD50）为5000mg/kg。因此，对配体235414以及亚胺培南进行了分子对接，亚胺培南属于相同的V类毒性等级，优化剂量（LD50）为5000mg/kg。亚胺培南是一种常用的美国食品药品监督管理局（FDA）批准用于治疗尿路感染的药物，在本研究中作为对照。与亚胺培南对NDM - 1、NDM - 5和OXA - 48的对接分数分别为 - 3.41 kcal/mol、 - 3.99 kcal/mol和 - 6.36 kcal/mol相比，氧杂环十六烷 - 2 - 酮对β - 内酰胺酶蛋白显示出更高的结合亲和力，对接分数分别为 - 6.45 kcal/mol、 - 6.05 kcal/mol和 - 7.34 kcal/mol。对氧杂环十六烷 - 2 - 酮和亚胺培南结合的蛋白复合物进行了100纳秒的动态模拟，以确定其稳定性、波动情况、紧凑性、键相互作用、溶剂可及面积、自由能景观以及结合自由能。分子对接和动力学结果表明氧杂环十六烷 - 2 - 酮具有良好前景，表明其对产β - 内酰胺酶蛋白具有强大的抑制作用。
