Discovery of Catechol-Benzothiazole Conjugates as Antibacterial Synergists against Pseudomonas aeruginosa by Inhibiting Biofilm Formation

The formation of Pseudomonas aeruginosa ( P. aeruginosa ) biofilm hinders the efficacy of antibiotics, making clinical treatment challenging. Given that disrupting iron homeostasis represents a promising strategy for treating biofilm infections, a series of catechol-conjugated benzothiazole derivatives with iron-chelating properties was designed and synthesized. Among them, 4p was identified as the hit compound, demonstrating potent biofilm inhibition (IC 50 = 0.27 μM). Mechanistic studies demonstrated that 4p attenuates biofilm formation by inhibiting heme oxygenase (HemO), impairing iron homeostasis, virulence factor production, and motility. Moreover, 4p synergized with ciprofloxacin (CIP) and tobramycin (Tob), enhancing their efficacy and delaying the development of resistance. Notably, 4p improved survival in Galleria mellonella ( G. mellonella ) and reduced bacterial load by 2.10–2.11log 10 CFU in mice wounds in vivo when combined with CIP and Tob. Collectively, these results highlight the potential of 4p as an antibacterial synergist and a promising candidate for the treatment of P. aeruginosa infections.