Dequalinium chloride promotes the killing efficacy of aminoglycoside antibiotics against Pseudomonas aeruginosa by enhancing membrane potential.

Dequalinium chloride is a dicationic amphiphilic quaternary ammonium compound that is used as an anti-infective drug. Here, we found that it potentiates bactericidal efficacies of aminoglycoside antibiotics against Pseudomonas aeruginosa. Dequalinium chloride increases respiratory activity and bacterial membrane potential, thereby promoting intracellular uptake of aminoglycosides. Furthermore, the dequalinium chloride-amikacin combination demonstrated a synergistic bactericidal effect in a murine acute pneumonia model, indicating its therapeutic potential.IMPORTANCEAntimicrobial resistance (AMR) poses a severe global health threat. Novel antibiotics and therapeutic strategies are urgently needed. This study revealed that dequalinium chloride (DC) synergizes with aminoglycosides against planktonic and biofilm-associated P. aeruginosa, which is an important pathogen. Mechanistic study reveals that DC enhances bacterial respiration and membrane potential to promote aminoglycosides uptake. The DC-amikacin combination is effective in a murine pneumonia model. These findings provide a promising therapeutic strategy for combating P. aeruginosa infections.