Background: Emergence, prevalence and widely spread of plasmid-mediated colistin resistance in Enterobacteriaceae strongly impairs the clinical efficacy of colistin against life-threatening bacterial infections. Combinations of antibiotics and FDA-approved non-antibiotic agents represent a promising means to address the widespread emergence of antibiotic-resistant pathogens./nMethods: Herein, we investigated the synergistic activity between melatonin and antibiotics against MCR (mobilized colistin resistance)-positive Gram-negative pathogens through checkerboard assay and time-killing curve. Molecular mechanisms underlying its mode of action were elucidated. Finally, we assessed the in vivo efficacy of melatonin in combination with colistin against drug-resistant Gram-negative bacteria./nResults: Melatonin, which has been approved for treating sleep disturbances and circadian disorders, substantially potentiates the activity of three antibiotics, particularly colistin, against MCR-expressing pathogens without enhancing its toxicity. This is evidence that the combination of colistin with melatonin enhances bacterial outer membrane permeability, promotes oxidative damage and inhibits the effect of efflux pumps. In three animal models infected by mcr-1-carrying E. coli, melatonin dramatically rescues colistin efficacy./nConclusion: Our findings revealed that melatonin serves as a promising colistin adjuvant against MCR-positive Gram-negative pathogens.

中文翻译：

---

褪黑素克服了革兰氏阴性病原体中MCR介导的粘菌素抗性。

背景：肠杆菌科细菌介导的大肠菌素耐药性的出现，盛行和广泛传播，大大削弱了大肠菌素对威胁生命的细菌感染的临床疗效。抗生素和FDA批准的非抗生素药物的组合代表了解决抗生素耐药性病原体广泛出现的有前途的方法。/n方法：在本文中，我们研究了褪黑激素和抗生素之间针对MCR（动员的大肠粘液抗性）阳性的协同活性。革兰氏阴性病原体通过棋盘检测和杀灭时间曲线。阐明了其作用方式的分子机制。最后，我们评估了体内在用针对耐药革兰阴性bacteria./n粘菌素联合褪黑素功效结果：褪黑激素，其已被批准用于治疗睡眠障碍和昼夜节律失调，基本上potentiates的三种抗生素，活性尤其粘菌素，对MCR表达病原体而不增强其毒性。这证明大肠菌素与褪黑激素的结合可增强细菌的外膜通透性，促进氧化损伤并抑制外排泵的作用。在三种携带mcr-1的大肠杆菌感染的动物模型中，褪黑激素可以显着地恢复大肠杆菌的功效。/n结论： 我们的研究结果表明，褪黑激素可作为针对MCR阳性革兰氏阴性病原体的大肠粘菌素佐剂。