Abstract

Antibiotic resistance is a global problem nowadays and in 2017 the World Health Organization published the list of bacteria for which treatment are urgently needed, where Pseudomonas aeruginosa is of critical priority. Current therapies lack efficacy because this organism creates biofilms conferring increased resistance to antibiotics and host immune responses. The strategy is to “not kill, but disarm” the pathogen and resistance will be developed slowly. It has been shown that LasI/LasR system is the main component of the quorum sensing system in P. aeruginosa. LasR is activated by the interaction with its native autoinducer. A lot flavones and their derivatives are used as antibacterial drug compounds. The purpose is to search compounds that will inhibit LasR. This leads to the inhibition of the synthesis of virulence factors thus the bacteria will be vulnerable and not virulent. We performed virtual screening using AutoDock Vina, rDock, LeDock for obtaining consensus predictions. The results of virtual screening suggest benzamides which are synthetical derivatives of flavones as potential inhibitors of transcriptional regulator LasR. These are consistent with recently published experimental data, which demonstrate the high antibacterial activity of benzamides. The compounds interact with the ligand binding domain of LasR with higher binding affinity than with DNA binding domain. Among the selected compounds, by conformational analysis, it was found that there are compounds that bind to the same amino acids of ligand binding domain as the native autoinducer. This could indicate the possibility of competitive interaction of these compounds. A number of compounds that bind to other conservative amino acids ligand binding domain have also been discovered, which will be of interest for further study. Selected compounds meet the criteria necessary for their consideration as drugs and can serve as a basis for conducting further in vitro/in vivo experiments. It could be used for the development of modern anti-infective therapy based on the quorum sensing system of P. aeruginosa.

中文翻译：

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在计算机上筛选黄酮及其衍生物作为铜绿假单胞菌的群体感应调节因子LasR的潜在抑制剂

摘要

如今，抗生素耐药性已成为全球性问题，世界卫生组织于2017年发布了急需治疗的细菌清单，其中铜绿假单胞菌是至关重要的。当前的疗法缺乏功效，因为这种生物体会形成生物膜，从而赋予抗生素更大的抗药性和宿主免疫反应。策略是“不杀死，但解除武装”，病原体和耐药性将缓慢发展。研究表明，LasI / LasR系统是铜绿假单胞菌群体感应系统的主要组成部分。。LasR通过与其天然自诱导剂的相互作用而被激活。许多黄酮及其衍生物被用作抗菌药物化合物。目的是寻找可抑制LasR的化合物。这导致抑制毒力因子的合成，因此细菌将是脆弱的而不是有毒的。我们使用AutoDock Vina，rDock，LeDock进行了虚拟筛选，以获得共识预测。虚拟筛选的结果表明，苯甲酰胺是黄酮的合成衍生物，是潜在的转录调节因子LasR抑制剂。这些与最近发表的实验数据一致，后者证明了苯甲酰胺具有很高的抗菌活性。该化合物与LasR的配体结合域相互作用的结合亲和力高于与DNA结合域的结合亲和力。通过构象分析，在选择的化合物中，发现存在与天然自体诱导剂结合的配体结合结构域相同氨基酸的化合物。这可能表明这些化合物竞争性相互作用的可能性。还发现了许多与其他保守氨基酸配体结合结构域结合的化合物，这将有待进一步研究。所选化合物符合将其视为药物所必需的标准，并且可以用作进行进一步的体内/体外实验的基础。基于群体群体感应系统可以用于现代抗感染治疗的发展。这可能表明这些化合物竞争性相互作用的可能性。还发现了许多与其他保守氨基酸配体结合结构域结合的化合物，这将有待进一步研究。所选化合物符合将其视为药物所必需的标准，并且可以用作进行进一步的体内/体外实验的基础。基于群体群体感应系统可以用于现代抗感染治疗的发展。这可能表明这些化合物竞争性相互作用的可能性。还发现了许多与其他保守氨基酸配体结合结构域结合的化合物，这将有待进一步研究。所选化合物符合将其视为药物所必需的标准，并且可以用作进行进一步的体内/体外实验的基础。基于群体群体感应系统可以用于现代抗感染治疗的发展。所选化合物符合将其视为药物所必需的标准，并且可以用作进行进一步的体内/体外实验的基础。基于群体群体感应系统可以用于现代抗感染治疗的发展。所选化合物符合将其视为药物所必需的标准，并且可以用作进行进一步的体内/体外实验的基础。基于群体群体感应系统可以用于现代抗感染治疗的发展。铜绿假单胞菌。