Department of Biotechnology, D.G. Vaishnav College, Arumbakkam, Chennai, 600106, India.
Shandong University - Helmholtz Institute of Biotechnology, State Key Laboratory of Microbial Technology, School of Life Science, Shandong University - Qingdao Campus, Aoshanwei, PR China.
Microb Pathog. 2019 May;130:104-111. doi: 10.1016/j.micpath.2019.02.037. Epub 2019 Mar 5.
Emergence of multi-drug resistant bacterial pathogens is escalating and it is essential to develop novel strategies to combat these super bugs. LasR is a regulator switch that plays a vital role in quorum sensing (QS) and pathogenesis of Pseudomonas aeruginosa. The present study reports two novel Mannich base (1-(phenyl (o-tolylamino) methyl) urea and 3-((1H-Imidazole-1-yl) methylnaphthalene-2-ol with enhanced anti-QS and antibiofilm activities. Synthetic compound revealed prolific interaction patterns with LasR quorum sensing receptor and showed to exhibit LasR antagonistic activities in P. aeruginosa. In-vitro LasR-inhibitory activities were further confirmed by biofilm and pyocyanin inhibition assays which showed a dose-dependent activity. The Mannich base also repressed the mRNA transcripts levels of lasA and lasB genes, confirming its active role in LasR inhibitory activity. Importantly, C1 and C2 played a crucial role in antagonizing LasR receptor by forming H-bonds with Tyr in the LasR active site and the presence of urea moiety on one of the Mannich base was a discrete advantage. Taken together, the insilico and invitro assays revealed similar evidences, thus confirming the mode of action of the Mannich bases. Overall the findings will assist in drug designing and for developing newer drugs with Mannich bases and its derivatives for treatment of P. aeruginosa.
耐药细菌病原体的出现呈上升趋势，因此必须开发新的策略来对抗这些超级细菌。LasR 是一种调节开关，在铜绿假单胞菌的群体感应 (QS) 和发病机制中起着至关重要的作用。本研究报告了两种新型曼尼希碱 (1-(苯基 (邻甲苯氨基) 甲基) 脲和 3-((1H-咪唑-1-基)甲基萘-2-醇)，具有增强的抗 QS 和抗生物膜活性。合成化合物与 LasR 群体感应受体显示出丰富的相互作用模式，并表现出对铜绿假单胞菌的 LasR 拮抗活性。通过生物膜和绿脓菌素抑制测定进一步证实了体外 LasR 抑制活性，显示出剂量依赖性活性。曼尼希碱还抑制了 lasA 和 lasB 基因的 mRNA 转录本水平，证实了其在 LasR 抑制活性中的积极作用。重要的是，C1 和 C2 通过与 LasR 活性位点中的 Tyr 形成氢键，在拮抗 LasR 受体方面发挥了关键作用，而曼尼希碱上脲部分的存在是一个明显的优势。总之，计算机和体内研究结果都提供了类似的证据，从而证实了曼尼希碱的作用模式。总的来说，这些发现将有助于药物设计，并开发出含有曼尼希碱及其衍生物的新型药物，用于治疗铜绿假单胞菌。
