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.