Docking analysis insights quercetin can be a non-antibiotic adjuvant by inhibiting Mmr drug efflux pump in <i>Mycobacterium</i> sp. and its homologue EmrE in <i>Escherichia coli</i>

Drug efflux pumps (EP) like Mmr in <i>Mycobacterium</i> transported drugs out of cell, a main reason for drug resistance developing in <i>Mycobacterium tuberculosis</i>. In this <i>in silico</i> study, mainly analysed EP inhibitory potential of a plant-derived flavonoid, quercetin, through docking analysis. Mmr present in <i>Mycobacterium smegmatis</i> and <i>M. tuberculosis,</i> and its homologue EmrE of <i>Escherichia coli</i> was used<i>.</i> Initially, homology modelling of EP monomers and dimers constructed from <i>M. smegmatis</i>, <i>M. tuberculosis</i> and <i>E. coli</i>; the stabilities of models were analysed from Ramachandran plots prepared in PROCHECK. Docking analysis of quercetin with EP protein showed that in all three organisms, the residues for function and stability are important and quercetin had best interactions comparing to compounds such as, verapamil, reserpine, chlorpromazine, Carbonyl Cyanide m- Chloro Phenylhydrazone. Molecular dynamics and simulation studies showed that during the entire course of simulation quercetin-Mmr complex were stable. It insights quercetin can act as a non-antibiotic adjuvant for treatment of tuberculosis by bring down the efflux of drug from bacteria.

药物外排泵（Drug efflux pumps, EP）如分枝杆菌属（Mycobacterium）中的Mmr可将药物泵出胞外，这是结核分枝杆菌（Mycobacterium tuberculosis）产生耐药性的主要诱因之一。本项计算机模拟（in silico）研究主要通过分子对接分析，评估了植物来源黄酮类化合物槲皮素（quercetin）的外排泵抑制潜力。耻垢分枝杆菌（Mycobacterium smegmatis）和结核分枝杆菌中均存在Mmr，本研究同时以大肠杆菌（Escherichia coli）的同源蛋白EmrE作为研究对象。首先，我们对来源于耻垢分枝杆菌、结核分枝杆菌和大肠杆菌的外排泵单体与二聚体进行同源建模；通过PROCHECK软件生成的拉马钱德兰图（Ramachandran plots）分析了所构建模型的稳定性。槲皮素与外排泵蛋白的分子对接分析结果显示，在三种受试微生物中，与蛋白功能及稳定性相关的氨基酸残基均发挥关键作用，且槲皮素与靶蛋白的相互作用优于维拉帕米（verapamil）、利血平（reserpine）、氯丙嗪（chlorpromazine）、羰基氰化物间氯苯腙（Carbonyl Cyanide m-Chloro Phenylhydrazone）等化合物。分子动力学模拟研究表明，在整个模拟周期内，槲皮素-Mmr复合物始终保持稳定。本研究提示，槲皮素可作为非抗生素佐剂，通过抑制细菌的药物外排过程用于结核病的辅助治疗。