Potent synergistic efficacy of 2-methoxy-1,4-naphthoquinone derived from quinones against drug-resistant bacteria

Abstract

The emergence and worldwide dissemination of mobile tigecycline resistance genes tet(X3)/tet(X4) posed an enormous threat to the public health. Urgently, feasible strategies must be implemented to restore the clinical efficacy of tetracyclines and prolong the lifespan of existing drugs to address the emerging global antimicrobial resistance threat. Herein, versatile structural scaffolds of quinones for antibiotic adjuvants discovery enlightened a promising and underappreciated reservoir to circumvent the antibiotic resistance. 2-methoxy-1,4-naphthoquinone (MNQ) exhibited the potent potentiation (4 to 32-fold) with tetracyclines, along with effective inhibition on biofilm formation. Mechanistic studies revealed that MNQ synergistically operates with tetracyclines by inhibiting the enzymatic activity of Tet(X3)/Tet(X4) proteins through interaction with their active residues. Furthermore, exposure to MNQ significantly dissipate the proton motive force, leading to a cascade of membrane structural damage and metabolic homeostasis imbalance. Encouragingly, the MNQ-tetracyclines combination showcased substantial therapeutic benefits in two in vivo infection models, as evidenced by the reduced bacterial burden and mitigated pathological injury. Our findings propose a potential therapeutic option and a novel tetracyclines' adjuvant against drug-resistant pathogens carrying Tet(X3)/Tet(X4).