In Silico and in Vitro-Guided Identification of Inhibitors of Alkylquinolone-Dependent Quorum Sensing in Pseudomonas aeruginosa.
In Silico and in Vitro-Guided Identification of Inhibitors of Alkylquinolone-Dependent Quorum Sensing in Pseudomonas aeruginosa.
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DOI：
10.3390/molecules23020257
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发表时间：
2018-01-28
期刊：
影响因子：
--
通讯作者：
Cámara M
中科院分区：
文献类型：
--
作者：
Soukarieh F;Vico Oton E;Dubern JF;Gomes J;Halliday N;de Pilar Crespo M;Ramírez-Prada J;Insuasty B;Abonia R;Quiroga J;Heeb S;Williams P;Stocks MJ;Cámara M
铜绿假单胞菌（Pseudomonas aeruginosa）是囊性纤维化、伤口和医院感染的主要条件致病菌，其抗生素耐药性对公共卫生造成严重负担。P. aeruginosa Pseudomonas Quinolone System （pqs）群体感应系统是由烷基喹诺酮（AQ）信号分子激活转录调控因子PqsR （MvfR）驱动的，在毒力调控中起关键作用，是开发新型抗菌药物的潜在靶点。在这项研究中，我们进行了硅对接分析，结合使用铜绿假单胞菌mCTX::PpqsA-lux染色体启动子融合筛选，鉴定了一系列新的PqsR拮抗剂。这些化合物抑制了铜绿假单胞菌PAO1-L和PA14菌株的花青素和烷基喹诺酮类信号分子的产生。在PA14中表现出最高活性的抑制剂Ia减少了PAO1-L和PA14的生物膜形成，增加了它们对妥布霉素的敏感性。此外，这些化合物的肝脏和血浆稳定性在大鼠和人体外微粒体测定中确定，以进一步了解其治疗潜力。这项工作已经发现了一类新的铜绿假单胞菌PqsR拮抗剂，具有潜在的打击，导致优化寻找群体感应抑制剂，为未来的抗感染药物发现计划。
Pseudomonas aeruginosa is a major opportunistic pathogen in cystic fibrosis, wound and nosocomial infections, posing a serious burden to public health, due to its antibiotic resistance. The P. aeruginosa Pseudomonas Quinolone System (pqs) quorum sensing system, driven by the activation of the transcriptional regulator, PqsR (MvfR) by alkylquinolone (AQ) signal molecules, is a key player in the regulation of virulence and a potential target for the development of novel antibacterial agents. In this study, we performed in silico docking analysis, coupled with screening using a P. aeruginosa mCTX::PpqsA-lux chromosomal promoter fusion, to identify a series of new PqsR antagonists. The hit compounds inhibited pyocyanin and alkylquinolone signal molecule production in P. aeruginosa PAO1-L and PA14 strains. The inhibitor Ia, which showed the highest activity in PA14, reduced biofilm formation in PAO1-L and PA14, increasing their sensitivity to tobramycin. Furthermore, the hepatic and plasma stabilities for these compounds were determined in both rat and human in vitro microsomal assays, to gain a further understanding of their therapeutic potential. This work has uncovered a new class of P. aeruginosa PqsR antagonists with potential for hit to lead optimisation in the search for quorum sensing inhibitors for future anti-infective drug discovery programs.
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影响因子：
6.7
作者：
Ilangovan A;Fletcher M;Rampioni G;Pustelny C;Rumbaugh K;Heeb S;Cámara M;Truman A;Chhabra SR;Emsley J;Williams P
通讯作者：
Williams P
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120.1
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影响因子：
120.7
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Marston, Hilary D.;Dixon, Dennis M.;Fauci, Anthony S.
通讯作者：
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