Novel 2-Substituted 3-Hydroxy-1,6-dimethylpyridin-4(1<i>H</i>)-ones as Dual-Acting Biofilm Inhibitors of <i>Pseudomonas aeruginosa</i>

Abstract

2-Heptyl-3-hydroxy-4(1<i>H</i>)-quinolone (PQS), a compound from <i>P. aeruginosa</i>, 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 <i>P. aeruginosa</i>. A series of 2-substituted 3-hydroxy-1,6-dimethylpyridin-4-ones have been designed, synthesized, and tested as biofilm inhibitors of <i>P. aeruginosa.</i> One compound, <i>N</i>-((1,3,6-trimethyl-4-oxo-1,4-dihydropyridin-2-yl)methyl)hexanamide (<b>10d</b>), exhibits 68.67% biofilm inhibitory activity at 20 μM. Further mechanistic studies have confirmed that this compound not only inhibits the QS systems of <i>P. aeruginosa</i> 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 <b>10d</b> by the <i>Pvds</i> mutant strain, <i>fpvA</i>-overexpressed strain, and <i>in silico</i> studies.