Cloxiquine exerts bactericidal activity against Enterococcus faecalis through disruption of proton motive force and induction of reactive oxygen species

BACKGROUND: The antibiotic resistance of Enterococcus faecalis (E. faecalis) continues to rise and spread globally, posing a severe challenge to clinical therapy and creating an urgent need for novel effective agents. RESULTS: Our findings demonstrated that Cloxiquine, an 8-hydroxyquinoline derivative, exhibited rapid bactericidal activity against E. faecalis with low propensity for resistance development. Furthermore, Cloxiquine could also inhibit the biofilm formation and showed great post-antibiotic effects against E. faecalis. Mechanistic studies revealed that Cloxiquine disrupted the transmembrane proton gradient, a main component of the proton motive force, thereby reducing ATP production and increasing reactive oxygen species accumulation. Meanwhile, Cloxiquine exhibited effective antimicrobial effects in vivo with an acceptable toxicity profile. CONCLUSION: Our results indicate that Cloxiquine could be a promising candidate for the treatment of E. faecalis-related refractory infections.