INTRODUCTION: With the increasing global challenge posed by multidrug-resistant Pseudomonas aeruginosa, which utilizes biofilm formation and virulence mechanisms to exacerbate infections, there is an urgent need for novel therapeutic strategies. OBJECTIVES: This work presents a novel dual-targeting biofilm inhibitor that potentiates antibiotic efficacy, offering a potent and safe candidate to combat P. aeruginosa infections. METHODS: To address this problem, we developed dual-targeting biofilm inhibitors that simultaneously disrupt the quorum sensing (QS) system and iron homeostasis system via computer-aided drug design. Through integrated in vitro screening and computational ADMET profiling, HK-34b, a 1-hydroxybenzimidazolone derivative, was identified. RESULTS: = 5.56 μM), the outer membrane receptor for siderophores. MD simulations revealed stable binding of HK-34b to both PqsR and FpvA. CONCLUSIONS: This dual-targeting strategy demonstrates significant translational potential by employing a novel chemical scaffold, which not only avoids the cross-resistance risks associated with the shared molecular scaffolds of conventional siderophore-antibiotic conjugates, but also overcomes the drawbacks of insufficient biofilm efficacy seen with single-target inhibitors, thereby providing a sustainable approach for the treatment of multidrug-resistant P. aeruginosa infections.
Chen et al. (Fri,) studied this question.