摘要
      抗生素耐药性基因（ARGs）的广泛传播是一个严重的问题，对公众健康构成威胁。质粒介导的ARGs偶联转移被认为是导致这场全球危机的最重要途径之一。抑制携带耐药基因的质粒的偶联转移为防止抗生素耐药性的传播提供了一种可行的策略。在这里，我们发现褪黑素，一种从松果体分泌的神经激素，以剂量依赖的方式显著抑制RP4-7质粒的水平转移。此外，褪黑素还可以抑制携带粘菌素抗性基因mcr-1而不是blaNDM或tet（X）基因的不同类型临床质粒的结合频率。接下来，我们研究了褪黑素抑制结合作用的机制。因此，我们发现褪黑素的添加显著降低了细菌膜的通透性，并抑制了氧化应激。根据这些观察结果，偶联转移相关基因受到了相应的调控。最重要的是，我们发现褪黑素破坏了细菌质子原动力（PMF），PMF是细菌能量代谢的重要物质，对结合过程很重要。总的来说，这些结果表明，一些非抗生素，如褪黑素，是ARGs传播的有效抑制剂，并提出了一种有希望的策略来应对日益增加的耐药性感染。
Abstract
The widespread dissemination of antibiotic resistance genes (ARGs) is a serious problem and constitutes a threat for public health. Plasmid-mediated conjugative transfer of ARGs is recognized as one of the most important pathways accounting for this global crisis. Inhibiting the conjugative transfer of resistant gene-bearing plasmids provides a feasible strategy to prevent the spread of antibiotic resistance. Here we found that melatonin, a neurohormone secreted from pineal gland, substantially inhibited the horizontal transfer of RP4–7 plasmid in a dose-dependent manner. Furthermore, melatonin could also suppress the conjugal frequency of different types of clinical plasmids that carrying colistin resistance gene mcr-1 rather than blaNDM or tet(X) genes. Next, we investigated the mechanisms underlying the inhibitory effect of melatonin on conjugation. As a result, we showed that the addition of melatonin markedly reduced bacterial membrane permeability and inhibited the oxidative stress. In line with these observations, the conjugative transfer-related genes were regulated accordingly. Most importantly, we uncovered that melatonin disrupted bacterial proton motive force (PMF), which is an essential bacterial energy metabolism substance and is important for conjugative process. Collectively, these results provide implications that some non-antibiotics such as melatonin are effective inhibitors of transmission of ARGs and raise a promising strategy to confront the increasing resistant infections.

https://www.sciencedirect.com/science/article/abs/pii/S1043661821005624