摘要

抗生素耐药性是对公众健康的严重全球威胁，每年造成约70万人死亡。水平基因转移（HGT）是传播抗生素抗性的最重要途径之一。人们普遍认为，抗生素的亚最小抑制浓度是通过HGT促进抗生素抗性的主要因素。药物在我们的环境中以更高的水平发生，但很少有人知道非抗生素药物是否会引起或加速抗生素耐药性的传播。在这里，我们首次报道抗癫痫药物卡马西平促进抗生素抗性基因的接合转移。可以看出，环境相关浓度的卡马西平（例如，0.05mg / L）显着增强了质粒携带的细菌属内和跨细菌属的多抗性基因的接合转移。通过检测氧化应激和细胞膜通透性，结合MinION DNA测序，全基因组RNA测序和蛋白质组学分析，揭示了增强HGT的潜在机制。卡马西平诱导了一系列急性反应，包括活性氧水平升高，SOS反应;增加细胞膜通透性和菌毛生成。在卡马西平暴露期间，与这些过程相关的基因的表达水平显着上调。鉴于HGT在不同环境中的不同物种中广泛存在，这些发现是对非抗生素药物在抗生素抗性传播中作用的广泛评估的早期警告。

Antibiotic resistance is a severe global threat for public health, causing around 700,000 deaths per year. Horizontal gene transfer (HGT) is one of the most significant pathways to disseminate antibiotic resistance. It is commonly acknowledged that sub-minimum inhibition concentrations of antibiotics are major contributors in promoting antibiotic resistance through HGT. Pharmaceuticals are occurring in our environments at increased levels, yet little is known whether non-antibiotic pharmaceuticals cause or accelerate the dissemination of antibiotic resistance. Here, we report for the first time that the antiepileptic drug, carbamazepine, promotes conjugative transfer of antibiotic resistance genes. It was seen that environmentally relevant concentrations of carbamazepine (e.g., 0.05 mg/L) significantly enhanced the conjugative transfer of multiresistance genes carried by plasmid within and across bacterial genera. The underlying mechanisms of the enhanced HGT were revealed by detecting oxidative stress and cell membrane permeability, in combination with MinION DNA sequencing, genome-wide RNA sequencing, and proteomic analysis. Carbamazepine induced a series of acute responses, including increased levels of reactive oxygen species, the SOS response; increased cell membrane permeability, and pilus generation. Expressional levels of genes related to these processes were significantly upregulated during carbamazepine exposure. Given that HGT occurs widely among different species in various environments, these findings are an early warning for a wide assessment of the roles of non-antibiotic pharmaceuticals in the spread of antibiotic resistance.

https://www.ncbi.nlm.nih.gov/pubmed/30291330