Departamento de Microbiología e Inmunología, Facultad de Ciencias Biológicas, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, Nuevo León, México.
Department of Microbiology, Faculty of Basic and Applied Sciences, Osun State University, Osogbo, Nigeria.
J Biomol Struct Dyn. 2023 Mar;41(5):1776-1789. doi: 10.1080/07391102.2021.2024261. Epub 2022 Jan 7.
The AcrAB-TolC efflux pump (EP) confers multidrug resistance to , a major etiological agent of foodborne infections. Phytochemicals that inhibit the functions of AcrAB-TolC EP present ideal candidates for reversal of antibiotic resistance. Progressive technological advancements, have facilitated the development of computational methods that offer a rapid low-cost approach to screen and identify phytochemicals with inhibitory potential against EP. In this study, 71 phytochemicals derived from plants used for medicinal purposes in Mexico were screened for their potential as inhibitors of AcrB protein using approaches including molecular docking and molecular dynamics (MD) simulation. Consequently, naringenin, 5-methoxypsoralen, and licarin A were identified as candidate inhibitors of AcrB protein. The three phytochemicals bound distal/deep pocket (DP) and hydrophobic trap (HPT) residues of AcrB protein critical for interactions with inhibitors, with estimated binding free energies of -95.5 kJ/mol, -97.4 kJ/mol, and -143.8 kJ/mol for naringenin, 5-methoxypsoralen, and licarin A, respectively. Data from the 50 ns MD simulation study revealed stability of the protein-ligand complex and alterations in the AcrB protein DP conformation upon binding of phytochemicals to the DP and HPT regions. Based on the estimated binding free energy and interactions with three out of five residues lining the hydrophobic trap, licarin A demonstrated the highest inhibitory potential, supporting its further application as a candidate for overcoming drug resistance in pathogens. Communicated by Ramaswamy H. Sarma.
AcrAB-TolC 外排泵（EP）赋予 对抗生素的多重耐药性， 是食源性感染的主要病原体。抑制 AcrAB-TolC EP 功能的植物化学物质是逆转抗生素耐药性的理想候选物。技术的不断进步，促进了计算方法的发展，为筛选和鉴定具有抑制 EP 潜力的植物化学物质提供了快速、低成本的方法。在这项研究中，从墨西哥用于药用的植物中筛选出 71 种植物化学物质，使用包括分子对接和分子动力学（MD）模拟在内的方法，研究它们作为 AcrB 蛋白抑制剂的潜力。结果表明，柚皮素、5-甲氧基补骨脂素和甘草素 A 被鉴定为 AcrB 蛋白的候选抑制剂。这三种植物化学物质与 AcrB 蛋白的远/深口袋（DP）和疏水性陷阱（HPT）残基结合，这些残基对于与抑制剂的相互作用至关重要，柚皮素、5-甲氧基补骨脂素和甘草素 A 的结合自由能估计分别为-95.5 kJ/mol、-97.4 kJ/mol 和-143.8 kJ/mol。来自 50 ns MD 模拟研究的数据表明，蛋白质-配体复合物的稳定性以及 AcrB 蛋白 DP 构象的改变，当植物化学物质结合到 DP 和 HPT 区域时。基于估计的结合自由能和与 5 个疏水陷阱残基中的 3 个的相互作用，甘草素 A 表现出最高的抑制潜力，支持其进一步作为克服病原体中药物耐药性的候选物的应用。由 Ramaswamy H. Sarma 传达。
