Hybrid Molecules of Benzothiazole and Hydroxamic Acid as Dual-Acting Biofilm Inhibitors with Antibacterial Synergistic Effect against Pseudomonas aeruginosa Infections

The ubiquitous opportunistic pathogen Pseudomonas aeruginosa (P. aeruginosa) causes biofilm-associated drug-resistant infections that often lead to treatment failure. Targeting the bacterium's quorum sensing (QS) and iron homeostasis presents a promising strategy to combat biofilm formation. This study synthesized benzothiazole-conjugated hydroxamic acid derivatives as dual-acting biofilm inhibitors, and compound JH21 was identified as the hit compound with potent submicromolar biofilm inhibitory activity (IC50 = 0.4 μM). Further mechanistic studies demonstrated not only that the production of virulence was decreased through mainly inhibiting QS system but also that JH21 competed for iron with the high-affinity siderophore pyoverdine, inducing iron deficiency and inhibiting biofilm. Moreover, JH21 significantly enhanced the efficacy of tobramycin and ciprofloxacin by 200- and 1000-fold, respectively, in a mouse wound infection model. These results emphasized the feasibility of dual-acting biofilm inhibitors against resistant P. aeruginosa infections and the potential of JH21 as a novel antibacterial synergist.