Design, synthesis and biological evaluation of 2-substituted 3-hydroxy-6-methyl-4H-pyran-4-one derivatives as Pseudomonas aeruginosa biofilm inhibitors
Design, synthesis and biological evaluation of 2-substituted 3-hydroxy-6-methyl-4H-pyran-4-one derivatives as Pseudomonas aeruginosa biofilm inhibitors
复制标题
2-取代3-羟基-6-甲基-4H-吡喃-4-酮衍生物作为铜绿假单胞菌生物膜抑制剂的设计、合成和生物学评价
DOI：
10.1016/j.ejmech.2018.09.041
复制
发表时间：
2018-10-05
影响因子：
6.7
通讯作者：
Chen, Wei-Min
中科院分区：
文献类型：
--
作者：
Li, Yi-Bin;Liu, Jun;Chen, Wei-Min
与生物膜形成相关的耐药细菌迅速增加，需要新的治疗方案来对抗生物膜诱导的耐药性。在本研究中，通过对内部化合物文库的筛选，发现一类3-hydroxy-2-(phenylhydroxy-methyl)-6-methyl-4H-pyran-4-one衍生物(1a-le)是潜在的铜绿假单胞菌生物被膜抑制剂。合成了31个新的2-取代3-羟基-6-甲基-4H-吡喃-4-酮衍生物，并测定了它们的生物被膜抑制活性。进一步的机制研究表明，6a只对pqsA-GFP在荧光报告菌株中的表达和PQS调节的毒力因子绿青素的产生有抑制作用。这表明这类化合物通过PQS途径特异性地发挥其抗生物被膜活性。这里描述了新的化学生物被膜抑制剂，防止与铜绿假单胞菌感染相关的生物被膜形成。(C)2018年爱思唯尔·马森SAS。版权所有。
Drug-resistant bacteria associated with biofilm formation are rapidly on the rise, requiring novel therapeutic options to combat biofilm induced drug-resistance. In this study, a class of 3-hydroxy-2-(phenylhydroxy-methyl)-6-methyl-4H-pyran-4-one derivatives (1a-le) were found by screening of an in-house compound library to be potential Pseudomonas aeruginosa biofilm inhibitors. Thirty one novel 2-substituted 3-hydroxy-6-methyl-4H-pyran-4-one derivatives were synthesized and assayed for their biofilm inhibitory activity. A promising biofilm inhibitor 6a was identified, and showed an obvious biofilm inhibitory effect even at a concentration of 2.5 mu M. Further mechanism studies revealed that 6a only shows inhibitory effects on the expression of pqsA-gfp in a fluorescent reporter strain, and the production of a PQS- regulated virulence factor, pyocyanin. This indicates that this type of compound exercises its anti-biofilm activity specifically through the PQS pathway. Novel chemical biofilm inhibitors are described here and guard against biofilm formation associated with Pseudomonas aeruginosa infections. (C) 2018 Elsevier Masson SAS. All rights reserved.