BACKGROUND: A novel plasmid-mediated resistance-nodulation-division (RND) efflux pump gene cluster tmexCD1-toprJ1 in Klebsiella pneumoniae tremendously threatens the use of convenient therapeutic options in the post-antibiotic era, including the "last-resort" antibiotic tigecycline. RESULTS: In this work, the natural alkaloid harmaline was found to potentiate tigecycline efficacy (4- to 32-fold) against tmexCD1-toprJ1-positive K. pneumoniae, which also thwarted the evolution of tigecycline resistance. Galleria mellonella and mouse infection models in vivo further revealed that harmaline is a promising candidate to reverse tigecycline resistance. Inspiringly, harmaline works synergistically with tigecycline by undermining tmexCD1-toprJ1-mediated multidrug resistance efflux pump function via interactions with TMexCD1-TOprJ1 active residues and dissipation of the proton motive force (PMF), and triggers a vicious cycle of disrupting cell membrane integrity and metabolic homeostasis imbalance. CONCLUSION: These results reveal the potential of harmaline as a novel tigecycline adjuvant to combat hypervirulent K. pneumoniae infections.
Anti-Bacterial Agents , Drug Repositioning , Harmaline , Klebsiella Infections , Klebsiella pneumoniae , Tigecycline , Klebsiella pneumoniae/drug effects , Tigecycline/pharmacology , Klebsiella Infections/drug therapy , Klebsiella Infections/microbiology , Animals , Mice , Anti-Bacterial Agents/pharmacology , Harmaline/pharmacology , Harmaline/analogs & derivatives , Microbial Sensitivity Tests , Drug Resistance, Multiple, Bacterial , Bacterial Proteins/metabolism , Bacterial Proteins/genetics , Membrane Transport Proteins/metabolism , Membrane Transport Proteins/genetics , Female
