復(fù)旦大學(xué)上海醫(yī)學(xué)院英國(guó)籍全職長(zhǎng)江學(xué)者特聘教授、復(fù)旦大學(xué)生物醫(yī)學(xué)研究院研究員Alastair Murchie和研究員陳東戎率領(lǐng)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(diào)控的新型“核糖開(kāi)關(guān)”，該“開(kāi)關(guān)”對(duì)控制此類抗生素的“耐藥性”有重大作用,。
該成果符合開(kāi)發(fā)新型靶標(biāo)藥物的要求,，為人類最終攻克抗生素耐藥這一世紀(jì)難題提供了全新視角和理論依據(jù)，具有極大的臨床實(shí)用潛力,。近日,，最新一期世界頂級(jí)學(xué)術(shù)雜志《細(xì)胞》（《Cell》）以《新型氨基糖苷類抗生素核糖開(kāi)關(guān)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(yīng)用,，致病菌的耐藥性增強(qiáng),，找到“耐藥性如何形成的新機(jī)制”已成為各國(guó)科學(xué)家面臨的共同“世紀(jì)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(diào)控的新型“核糖開(kāi)關(guān)”,，有望攻克此難題,。
最新研究證明，“核糖開(kāi)關(guān)”是自然界細(xì)菌,、高等植物體內(nèi)天然存在的,、有調(diào)控作用的傳感器，位于細(xì)菌等體內(nèi)特定的基因非編碼區(qū),，它通過(guò)結(jié)合細(xì)菌等體內(nèi)小分子代謝物來(lái)調(diào)控基因的表達(dá),，可以不依賴任何蛋白質(zhì)因子而直接結(jié)合代謝物并發(fā)生結(jié)構(gòu)變化,，參與調(diào)控生物的基本代謝,。這一調(diào)控機(jī)制一經(jīng)發(fā)現(xiàn)，即刻引起各國(guó)科學(xué)家的高度關(guān)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.
