復旦大學上海醫(yī)學院英國籍全職長江學者特聘教授,、復旦大學生物醫(yī)學研究院研究員Alastair Murchie和研究員陳東戎率領的課題組,，歷經(jīng)3年多艱辛，終于在耐藥性病原菌中首次發(fā)現(xiàn)了一種由氨基糖苷類抗生素藥物調控的新型“核糖開關”,，該“開關”對控制此類抗生素的“耐藥性”有重大作用,。
該成果符合開發(fā)新型靶標藥物的要求，為人類最終攻克抗生素耐藥這一世紀難題提供了全新視角和理論依據(jù),，具有極大的臨床實用潛力,。近日，最新一期世界頂級學術雜志《細胞》（《Cell》）以《新型氨基糖苷類抗生素核糖開關的發(fā)現(xiàn)》為題,，刊發(fā)了這一重大發(fā)現(xiàn),。
隨著人類抗生素的廣泛應用，致病菌的耐藥性增強,，找到“耐藥性如何形成的新機制”已成為各國科學家面臨的共同“世紀難題”,，而該課題組此次發(fā)現(xiàn)的由氨基糖苷類抗生素藥物調控的新型“核糖開關”，有望攻克此難題,。
最新研究證明,，“核糖開關”是自然界細菌、高等植物體內天然存在的,、有調控作用的傳感器,，位于細菌等體內特定的基因非編碼區(qū),，它通過結合細菌等體內小分子代謝物來調控基因的表達，可以不依賴任何蛋白質因子而直接結合代謝物并發(fā)生結構變化,，參與調控生物的基本代謝,。這一調控機制一經(jīng)發(fā)現(xiàn)，即刻引起各國科學家的高度關注,。（生物谷Bioon.com）
doi:10.1016/j.cell.2012.12.019
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Riboswitch Control of Aminoglycoside Antibiotic Resistance
Xu Jia, Jing Zhang, Wenxia Sun, Weizhi He, Hengyi Jiang, Dongrong Chen, Alastair I.H. MurchieSee
Highlights
The 5′ leader RNA of aminoglycoside antibiotic-resistance genes is conserved
Aminoglycosides induce reporter gene expression by interacting with the leader RNA
The aminoglycosides bind to the leader RNA and induce a change in the RNA structure
Induction is independent of leader peptide stalling or drug-ribosome interactions
Summary
The majority of riboswitches are regulatory RNAs that regulate gene expression by binding small-molecule metabolites. Here we report the discovery of an aminoglycoside-binding riboswitch that is widely distributed among antibiotic-resistant bacterial pathogens. This riboswitch is present in the leader RNA of the resistance genes that encode the aminoglycoside acetyl transferase (AAC) and aminoglycoside adenyl transferase (AAD) enzymes that confer resistance to aminoglycoside antibiotics through modification of the drugs. We show that expression of the AAC and AAD resistance genes is regulated by aminoglycoside binding to a secondary structure in their 5′ leader RNA. Reporter gene expression, direct measurements of drug RNA binding, chemical probing, and UV crosslinking combined with mutational analysis demonstrate that the leader RNA functions as an aminoglycoside-sensing riboswitch in which drug binding to the leader RNA leads to the induction of aminoglycosides antibiotic resistance.
