抗抑郁药物度洛西汀和抗生素联合暴露对细菌抗生素抗性的影响及其作用机制研究

随着抗生素抗性细菌（ARB）成为当今全球面临的公共健康威胁，它在生态系统中的产生和传播机制也日益引起全球关注。通过前期研究，我们发现抗抑郁药物度洛西汀与抗生素协同促进大肠杆菌产生抗生素抗性，且ARB突变子的外排泵调节基因marR突变。针对此现象，本项目提出科学假设“度洛西汀和抗生素协同促进细菌产生抗生素抗性并与基因突变导致的细菌外排泵过表达有关”，并从环境污染和临床用药角度出发，阐明度洛西汀与抗生素协同促进环境和肠道ARB产生的规律，在利用转录组、基因组、代谢组等微生物组学和CRISPR-Cas9等基因编辑、三维超分辨显微技术等基础上，揭示ARB产生的基因调控网络及协同机制，充分验证假说。本项目将开辟环境和临床ARB产生机制研究新领域，丰富环境和临床ARB传播机制理论体系，为水中药物污染控制和临床控制ARB感染策略提供科学决策依据，推动公共卫生事业发展。

With antibiotic-resistant bacteria (ARB) becoming a global public health threat, its dissemination mechanism in ecosystem has attracted increasing global attention. In the previous studies, we found that antidepressant duloxetine and antibiotics can synergistically promote antibiotic resistance in environmental Escherichia coli, and several DNA mutations occurred in the efflux pump regulatory gene marR of ARB mutants. In response to this phenomenon, we first proposed the hypothesis that duloxetine and antibiotics can synergistically promote antibiotic resistance in bacteria and this effect is related to the overexpression of bacterial efflux pump caused by gene mutation. To fully validate this hypothesis and clarify the effect of duloxetine and antibiotics synergistically, taking into account environmental concentration and clinical dose, promoting the environmental and intestinal ARB production, the gene regulatory networks and synergistic mechanism to promote ARB production were revealed on the basis of microbiomics, fluorescence quantitative PCR, gene-editing technology, three-dimensional super-resolution microscopy, etc. This project will open up a new field for environmental and clinical ARB production mechanisms. It will not only enrich the theoretical system of environmental and clinical ARB transmission, but also provide scientific decision-making basis for drug contamination control in water and ARB control in clinic, promoting the development of public health.