Goh Wai-Kean, Gardner Christopher R, Chandra Sekhar Kondapalli V G, Biswas Nripendra N, Nizalapur Shashidhar, Rice Scott A, Willcox Mark, Black David StC, Kumar Naresh
School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia.
Department of Chemistry, Birla Institute of Technology & Science, Pilani, Hyderabad Campus, Hyderabad, Telangana 500078, India.
Bioorg Med Chem. 2015 Dec 1;23(23):7366-77. doi: 10.1016/j.bmc.2015.10.025. Epub 2015 Oct 23.
Gram-negative bacteria such as Pseudomonas aeruginosa and Escherichia coli use N-acylated l-homoserine lactones (AHLs) as autoinducers (AIs) for quorum sensing (QS), a chief regulatory and cell-to-cell communication system. QS is responsible for social adaptation, virulence factor production, biofilm production and antibiotic resistance in bacteria. Fimbrolides, a class of halogenated furanones isolated from the red marine alga Delisea pulchra, have been shown to exhibit promising QS inhibitory activity against various Gram-negative and Gram-positive bacterial strains. In this work, various lactam analogues of fimbrolides viz., 1,5-dihydropyrrol-2-ones, were designed and synthesized via an efficient lactamization protocol. All the synthesized analogues were tested for QS inhibition against the E. coli AHL-monitor strain JB357 gfp (ASV). Compound 17a emerged as the most potent compound, followed by 9c, with AIC40 values (the ratio of synthetic inhibitor to natural AHL signaling molecule that is required to lower GFP expression to 40%) of 1.95 and 19.00, respectively. Finally, the potential binding interactions between the synthesized molecules and the LasR QS receptor were studied by molecular docking. Our results indicate that 1,5-dihydropyrrol-2-ones have the ability to serve as potential leads for the further development of novel QS inhibitors as antimicrobial therapeutics.
革兰氏阴性菌，如铜绿假单胞菌和大肠杆菌，利用N-酰化-L-高丝氨酸内酯（AHLs）作为群体感应（QS）的自诱导剂（AIs），QS是一种主要的调节和细胞间通信系统。QS负责细菌的社会适应性、毒力因子产生、生物膜形成和抗生素抗性。从红色海藻美丽德尔藻中分离出的一类卤代呋喃酮——纤维内酯，已被证明对多种革兰氏阴性和革兰氏阳性细菌菌株具有有前景的QS抑制活性。在这项工作中，通过高效的内酰胺化方案设计并合成了纤维内酯的各种内酰胺类似物，即1,5-二氢吡咯-2-酮。对所有合成的类似物进行了针对大肠杆菌AHL监测菌株JB357 gfp（ASV）的QS抑制测试。化合物17a成为最有效的化合物，其次是9c，其AIC40值（将GFP表达降低到40%所需的合成抑制剂与天然AHL信号分子的比率）分别为1.95和19.00。最后，通过分子对接研究了合成分子与LasR QS受体之间的潜在结合相互作用。我们的结果表明，1,5-二氢吡咯-2-酮有能力作为新型QS抑制剂作为抗菌治疗药物进一步开发的潜在先导化合物。
