Cyclic Diguanylate G‑Quadruplex Inducer–Siderophore Hybrids as Bifunctional Antibiofilm Agents against Pseudomonas aeruginosa

Biofilm formation is a crucial determinant of both pathogenicity
and enhanced antibiotic resistance in Pseudomonas aeruginosa. Sustainable iron utilization in the bacterial growth environments
and intracellular c-di-GMP signaling molecules are key factors promoting
bacterial biofilm development. Capitalizing on our previous findings
that c-di-GMP G-quadruplex inducers exhibit potent antibiofilm activity
and that 3-hydroxypyridin-4(1H)-ones act as effective
iron chelators, we designed and synthesized dual-functional hybrid
molecules incorporating both pharmacophores. The lead compound 11f, which features a benzothiazole-pyridinone scaffold, demonstrated
potent biofilm inhibition against both wild-type P.
aeruginosa PAO1 and the hyper-biofilm-forming PAO1-ΔwspF mutant. Mechanistic investigations revealed that 11f operates through dual pathways: facilitating c-di-GMP
G-quadruplex formation and disrupting iron acquisition systems. Notably,
in Galleria mellonella infection models, 11f exhibited significant synergistic effects with ciprofloxacin
and tobramycin while maintaining an excellent safety profile, highlighting
its potential as an antibacterial adjuvant.