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.
CONCLUSIONS: These results reveal the potential of harmaline as a novel tigecycline adjuvant to combat hypervirulent K. pneumoniae infections.
结果:在这项工作中,发现天然生物碱harmaline可增强替加环素对tmexCD1-toprJ1阳性肺炎克雷伯菌的功效(4至32倍),这也阻碍了替加环素抗性的发展。Galleriamelonella和小鼠体内感染模型进一步显示,harmaline是逆转替加环素耐药性的有希望的候选者。鼓舞人心,harmaline与替加环素协同作用,通过与TmexCD1-TOprJ1活性残基的相互作用和质子动力(PMF)的耗散来破坏tmexCD1-toprJ1介导的多药耐药外排泵功能,并引发破坏细胞膜完整性和代谢稳态失衡的恶性循环。
结论:这些结果揭示了harmaline作为新型替加环素佐剂对抗高毒力肺炎克雷伯菌感染的潜力。