Hybrids of 3-Hydroxypyridin-4(1)-ones and Long-Chain 4-Aminoquinolines as Potent Biofilm Inhibitors of Potentiate Tobramycin and Polymyxin B Activity.

The biofilm formation of 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)-ones and long-chain 4-aminoquinolines were synthesized as biofilm inhibitors against based on a multipathway antibiofilm strategy. Comprehensive structure-activity relationship studies identified compound as the most valuable antagonist, which significantly inhibited biofilm formation (IC = 5.8 μM) and various virulence phenotypes. Mechanistic studies revealed that not only targets the three quorum sensing systems but also strongly induces iron deficiency signals in . Furthermore, demonstrated a favorable and safety profile. Moreover, specifically enhanced the antibacterial activity of tobramycin and polymyxin B in and combination therapy. Overall, these results highlight the potential of as a novel anti-infective candidate for treating infections.