Hybrids of 3-Hydroxypyridin-4(1<i>H</i>)-ones and Long-Chain 4-Aminoquinolines as Potent Biofilm Inhibitors of <i>Pseudomonas aeruginosa</i> Potentiate Tobramycin and Polymyxin B Activity
Zhiying Miao, Xiaoyi Zhang, Hao-Zhong Long, Jing Lin, Wei‐Min Chen
Abstract
The biofilm formation of Pseudomonas aeruginosa involves multiple complex regulatory pathways; thus, blocking a single pathway is unlikely to achieve the desired antibiofilm efficacy. Herein, a series of hybrids of 3-hydroxypyridin-4(1 H )-ones and long-chain 4-aminoquinolines were synthesized as biofilm inhibitors against P. aeruginosa based on a multipathway antibiofilm strategy. Comprehensive structure–activity relationship studies identified compound 30b as the most valuable antagonist, which significantly inhibited P. aeruginosa biofilm formation (IC 50 = 5.8 μM) and various virulence phenotypes. Mechanistic studies revealed that 30b not only targets the three quorum sensing systems but also strongly induces iron deficiency signals in P. aeruginosa . Furthermore, 30b demonstrated a favorable in vitro and in vivo safety profile. Moreover, 30b specifically enhanced the antibacterial activity of tobramycin and polymyxin B in in vitro and in vivo combination therapy. Overall, these results highlight the potential of 30b as a novel anti-infective candidate for treating P. aeruginosa infections.