Novel 2-Substituted 3-Hydroxy-1,6-dimethylpyridin-4(1H)-ones as Dual-Acting Biofilm Inhibitors of Pseudomonas aeruginosa
Novel 2-Substituted 3-Hydroxy-1,6-dimethylpyridin-4(1H)-ones as Dual-Acting Biofilm Inhibitors of Pseudomonas aeruginosa
复制标题
新型 2-取代 3-羟基-1,6-二甲基吡啶-4(1H)-酮作为铜绿假单胞菌的双效生物膜抑制剂
DOI：
10.1021/acs.jmedchem.0c00763
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发表时间：
2020-10-08
影响因子：
7.3
通讯作者：
Chen, Wei-Min
中科院分区：
文献类型：
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作者：
Liu, Jun;Hou, Jin-Song;Chen, Wei-Min
2-庚基-3-羟基-4(1H)-喹诺酮（PQS）是铜绿假单胞菌（P. aeruginosa）中的一种化合物，作为群体感应（QS）调节剂和铁螯合剂，可诱导参与高亲和铁转运系统的pyoverdine和pyochelin的表达。一种潜在的双作用抗生素膜策略需要设计干扰铜绿假单胞菌铁摄取和QS系统的分子。设计、合成了一系列2-取代的3-羟基-1,6-二甲基吡啶-4-酮，并对其作为铜绿假单胞菌的生物膜抑制剂进行了实验。其中一个化合物N-（（1,3,6-三甲基-4-氧-1,4-二氢吡啶-2-基）甲基）己胺（10d）在20 μ m的生物膜抑制活性为68.67%，进一步的机制研究证实该化合物不仅抑制P. aeruginosa的QS系统，而且作为铁螯合物与pyoverdine激烈竞争，导致细菌缺铁。通过Pvds突变株、FpvA过表达株和计算机实验，发现pyoverdine受体FpvA是10d的靶点。
2-Heptyl-3-hydroxy-4(1H)-quinolone (PQS), a compound from P. aeruginosa, functions as both a quorum sensing (QS) regulator and a potent iron chelator to induce expression of pyoverdine and pyochelin which are involved in high-affinity iron transport systems. A potential dual-acting antibiofilm strategy requires molecules designed to interfere with iron uptake and the QS system of P. aeruginosa. A series of 2-substituted 3-hydroxy-1,6-dimethylpyridin-4-ones have been designed, synthesized, and tested as biofilm inhibitors of P. aeruginosa. One compound, N-((1,3,6-trimethyl-4-oxo-1,4-dihydropyridin-2-yl)methyl)hexanamide (10d), exhibits 68.67% biofilm inhibitory activity at 20 mu M. Further mechanistic studies have confirmed that this compound not only inhibits the QS systems of P. aeruginosa but also acts as an iron chelator to compete strongly with pyoverdine, causing iron deficiency in bacteria. The pyoverdine receptor FpvA was revealed as the target of 10d by the Pvds mutant strain, fpvA-overexpressed strain, and in silico studies.