Biswas Nripendra N, Yu Tsz Tin, Kimyon Önder, Nizalapur Shashidhar, Gardner Christopher R, Manefield Mike, Griffith Renate, Black David StC, Kumar Naresh
School of Chemistry, University of New South Wales, Sydney, NSW, Australia.
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.
Bioorg Med Chem. 2017 Feb 1;25(3):1183-1194. doi: 10.1016/j.bmc.2016.12.024. Epub 2016 Dec 21.
Bacteria communicate with one another and regulate their pathogenicity through a phenomenon known as quorum sensing (QS). When the bacterial colony reaches a threshold density, the QS system induces the production of virulence factors and the formation of biofilms, a powerful defence system against the host's immune responses. The glucosamine monomer has been shown to disrupt the bacterial QS system by inhibiting autoinducer (AI) signalling molecules such as the acyl-homoserine lactones (AHLs). In this study, the synthesis of acetoxy-glucosamides 8, hydroxy-glucosamides 9 and 3-oxo-glucosamides 12 was performed via the 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) and N,N'-dicyclohexylcarbodiimide (DCC) coupling methods. All of the synthesized compounds were tested against two bacterial strains, P. aeruginosa MH602 (LasI/R-type QS) and E. coli MT102 (LuxI/R-type QS), for QS inhibitory activity. The most active compound 9b showed 79.1% QS inhibition against P. aeruginosa MH602 and 98.4% against E. coli MT102, while compound 12b showed 64.5% inhibition against P. aeruginosa MH602 and 88.1% against E. coli MT102 strain at 2mM concentration. The ability of the compounds to inhibit the production of the virulence factor pyocyanin and biofilm formation in the P. aeruginosa (PA14) strain was also examined. Finally, computational docking studies were performed with the LasR receptor protein.
细菌通过一种称为群体感应（QS）的现象相互交流并调节其致病性。当细菌菌落达到阈值密度时，QS系统会诱导毒力因子的产生和生物膜的形成，生物膜是抵御宿主免疫反应的强大防御系统。已证明氨基葡萄糖单体可通过抑制自诱导物（AI）信号分子如酰基高丝氨酸内酯（AHLs）来破坏细菌的QS系统。在本研究中，通过1-乙基-3-（3-二甲基氨基丙基）碳二亚胺盐酸盐（EDC·HCl）和N，N'-二环己基碳二亚胺（DCC）偶联方法合成了乙酰氧基氨基葡萄糖8、羟基氨基葡萄糖9和3-氧代氨基葡萄糖12。所有合成的化合物均针对两种细菌菌株铜绿假单胞菌MH602（LasI/R型QS）和大肠杆菌MT102（LuxI/R型QS）进行了QS抑制活性测试。活性最高的化合物9b对铜绿假单胞菌MH602的QS抑制率为79.1%，对大肠杆菌MT102的抑制率为98.4%，而化合物12b在2mM浓度下对铜绿假单胞菌MH602的抑制率为64.5%，对大肠杆菌MT102菌株的抑制率为88.1%。还研究了这些化合物抑制铜绿假单胞菌（PA14）菌株中毒力因子绿脓菌素产生和生物膜形成的能力。最后，对LasR受体蛋白进行了计算对接研究。
