European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2018-09-15 , DOI: 10.1016/j.ejmech.2018.09.041 Yi-Bin Li , Jun Liu , Zhi-Xing Huang , Jia-Hui Yu , Xiao-Fang Xu , Ping-Hua Sun , Jing Lin , Wei-Min Chen
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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-1e) 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 μM. 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.
中文翻译:
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铜绿假单胞菌生物膜抑制剂2-取代的3-羟基-6-甲基-4 H-吡喃-4-酮衍生物的设计,合成及生物学评价
与生物膜形成有关的耐药细菌正在迅速上升,需要新的治疗方法来对抗生物膜诱导的耐药性。在这项研究中,通过筛选内部化合物库,发现了一类3-羟基-2-(苯基羟基-甲基)-6-甲基-4 H-吡喃-4-酮衍生物(1a - 1e)。潜在的铜绿假单胞菌生物膜抑制剂。合成了三十一种新颖的2-取代的3-羟基-6-甲基-4 H-吡喃-4-酮衍生物,并对其生物膜抑制活性进行了测定。有前途的生物膜抑制剂6a经鉴定,即使在2.5μM的浓度下也显示出明显的生物膜抑制作用。进一步的机理研究表明,6a仅显示出对荧光报告株中pqsA-gfp表达的抑制作用,以及对PQS调节的致病因子黄绿素的产生的抑制作用。这表明这种类型的化合物特别是通过PQS途径行使其抗生物膜活性。本文描述了新型化学生物膜抑制剂,可防止与铜绿假单胞菌感染相关的生物膜形成。