Novel Coumarin Derivatives Inhibit the Quorum Sensing System and Iron Homeostasis as Antibacterial Synergists against <i>Pseudomonas aeruginosa</i>

Abstract

<i>Pseudomonas aeruginosa</i> (<i>P. aeruginosa</i>) is well-known to cause biofilm-associated drug resistance and infections that often lead to treatment failure. Herein, we reported a dual-acting antibiofilm strategy by inhibiting both the bacterial quorum sensing system and the iron uptake system. A series of coumarin derivatives were synthesized and evaluated, and compound <b>4t</b> was identified as the most effective biofilm inhibitor (IC₅₀ = 3.6 μM). Further mechanistic studies have confirmed that <b>4t</b> not only inhibits the QS systems but also competes strongly with pyoverdine as an iron chelator, causing an iron deficiency in <i>P. aeruginosa</i>. Additionally, <b>4t</b> significantly improved the synergistic antibacterial effects of ciprofloxacin and tobramycin by more than 200-1000-fold compared to the single-dose antibiotic treatments. Therefore, our study has shown that <b>4t</b> is a potentially novel antibacterial synergist candidate to treat bacterial infections.