抗生素耐药性在临床上日益巨增，只有全面地解析抗生素耐药性产生的机理，才能从根本上找到解决问题的方法。申请人的实验室在复旦大学于2013年1月在CELL杂志上首次报道了氨基糖苷类抗生素核糖开关调控其抗药性基因的表达，这是一个崭新的耐药性产生的机理，是世界上第一个与临床使用的抗生素直接关联的核糖开关。这个核糖开关是氨基糖苷类抗生素耐药性基因5’非编码区域的一段特殊的RNA序列，它可以与氨基糖苷类抗生素相结合引起RNA高级结构的改变从而调控其耐药性基因的表达。本项目将在发现和验证了此核糖开关的基础上，和英国的David Lilley 教授进行国际合作，通过使用X-衍射结晶的方法进一步解析此核糖开关的结构，用单分子荧光的技术观察此核糖开关的结构变化，继续深入研究此核糖开关的作用机理，为设计新型抑制耐药性的药物奠定理论基础，也为人类最终认识和战胜抗生素耐药性提供新的思维。

Antibiotic resistance is an increasing clinical problem. Understanding the mechanism of the antibiotic resistance is the key to this problem. The laboratory of the applicant in Fudan University reported that the aminoglycoside-sensing riboswitch control the expression of the aminoglycoside resistance gene. This is a new mechanism of antibiotic resistance and the first clinical relevant riboswitch in the world. This riboswitch RNA sequence is present in the 5’ untranslated mRNA and the binding of certain aminoglycoside to this RNA lead to a significant structure transition in the RNA which in turn result in changes in the down-stream gene expression. Based on the present experimental system, this project will be carried out in collaboration with Professor David Lilley at Dundee University UK. To investigate the mechanism of the aminoglycoside-sensing riboswitch, we will use X-ray crystallography technique to study the structure of the aminoglycoside-sensing riboswitch and also use single molecule FRET to observe the structural alteration up on binding of aminoglycoside. This work will be good foundation for future therapeutic intervention and provide new evidence for the mechanism of antibiotic resistance.