Department of Biochemistry, Biotechnology and Bioinformatics, Avinashilingam Institute for Home Science and Higher Education for Women, Coimbatore, 641043, Tamil Nadu, India.
Department of Pharmacy, National University of Singapore, Singapore 119077, Singapore.
Int Microbiol. 2023 Nov;26(4):851-868. doi: 10.1007/s10123-023-00338-0. Epub 2023 Feb 21.
The quorum sensing network of Pseudomonas aeruginosa mediates the regulation of genes controlling biofilm formation and virulence factors. The rise of drug resistance to Pseudomonas aeruginosa infections has made quorum sensing-regulated biofilm formation in clinical settings a major issue. In the present study, LasR inhibitors identified in our previous study were evaluated for their antibiofilm and antiquorum sensing activities against P. aeruginosa PAO1. The compounds selected were (3-[2-(3,4-dimethoxyphenyl)-2-(1H-indol-3-yl)ethyl]-1-(2-fluorophenyl)urea) (C1), (3-(4-fluorophenyl)-2-[(3-methylquinoxalin-2-yl)methylsulfanyl]quinazolin-4-one) (C2) and (2-({4-[4-(2-methoxyphenyl)piperazin-1-yl]pyrimidin-2-yl}sulfanyl)-N-(2,4,6-trimethylphenyl)acetamide) (C3). The minimum inhibitory concentrations of C1 and C2 were 1000 μM, whereas that of C3 was 500 μM. At sub-MICs, the compounds showed potent antibiofilm activity without affecting the growth of P. aeruginosa PAO1. Electron microscopy confirmed the disruption of biofilm by the selected compounds. The antiquorum sensing activity of the compounds was revealed by the inhibition of violacein in Chromobacterium violaceum and the inhibition of swimming and swarming motilities in P. aeruginosa PAO1. Furthermore, the compounds also attenuated the production of quorum sensing-mediated virulence factors. The qRT-PCR revealed the downregulation of quorum sensing regulatory genes, namely lasI, lasR, rhlI, rhlR, lasB, pqsA and pqsR. The selected compounds also exhibited lower cytotoxicity against peripheral blood lymphocytes. Thus, this study could pave a way to explore these compounds for the development of therapeutic agent against Pseudomonas aeruginosa biofilm-related infections.
铜绿假单胞菌的群体感应网络介导控制生物膜形成和毒力因子的基因调控。铜绿假单胞菌感染的耐药性上升使得临床环境中群体感应调节的生物膜形成成为一个主要问题。在本研究中，我们之前的研究中鉴定的 LasR 抑制剂被评估了其对 PAO1 铜绿假单胞菌的抗生物膜和抗群体感应活性。所选化合物为（3-[2-(3,4-二甲氧基苯基）-2-(1H-吲哚-3-基)乙基]-1-(2-氟苯基)脲）（C1），（3-(4-氟苯基)-2-[(3-甲基喹喔啉-2-基)甲硫基]喹唑啉-4-酮）（C2）和（2-({4-[4-(2-甲氧基苯基)哌嗪-1-基]嘧啶-2-基}硫基)-N-(2,4,6-三甲苯基)乙酰胺）（C3）。C1 和 C2 的最低抑菌浓度为 1000 μM，而 C3 的最低抑菌浓度为 500 μM。在亚 MIC 浓度下，这些化合物表现出很强的抗生物膜活性，而不影响 PAO1 铜绿假单胞菌的生长。电子显微镜证实了所选化合物对生物膜的破坏。化合物的抗群体感应活性通过抑制 Chromobacterium violaceum 中的紫色素和抑制 PAO1 铜绿假单胞菌的游泳和群集运动来揭示。此外，这些化合物还减弱了群体感应介导的毒力因子的产生。qRT-PCR 显示，群体感应调节基因 lasI、lasR、rhlI、rhlR、lasB、pqsA 和 pqsR 的表达下调。所选化合物对外周血淋巴细胞的细胞毒性也较低。因此，本研究为探索这些化合物开发治疗铜绿假单胞菌生物膜相关感染的治疗剂铺平了道路。
