细菌翻译修复通路（反式翻译）广泛存在于细菌且高度保守。当核糖体翻译遇到非终止mRNA时，细菌则启动主要由tmRNA-SmpB介导的翻译修复过程来拯救滞留在mRNA上的核糖体，使其解聚回收。最新研究表明，该修复通路对大部分病原菌的活力和毒力很重要，可作为潜在的抗生素靶点。已知几种重要的治疗肺结核的药物，如pyrazinamide和viomycin，以及新近发现的小分子药物KKL-35等均能抑制细菌反式翻译过程，从而起到抗菌效果。目前，反式翻译终止阶段的机制以及靶向反式翻译的抗生素的结合位点和作用机理尚未被研究清楚。基于此，申请人拟利用生物化学和结构生物方法深入研究：1.反式翻译终止阶段核糖体复合物的结构及机制；2.KKL-35和POA特异性抑制反式翻译的作用机理。3.viomycin作用于反式翻译的机制。该工作将推动对细菌反式翻译的理解并为基于核糖体复合物结构的新型抗菌药物设计提供重要依据。

Stalled translation rescue (trans-translation) is an essential and highly conserved pathway in bacteria cell. During translation, when the ribosome encountered a non-stop mRNA, the cell will initiate a process that was termed trans-translation to rescue the stalled ribosome and dissociate it into subunits. This process is mediated by a complex that consists of tmRNA and SmpB(small protein B). Recent studies showed that translation rescue pathway is highly significant for the viability and virulence of many pathogenic bacteria cell and is an attractive target for the development of antimicrobial agents. Inhibitors, such as pyrazinamide (PZA, a first line drug for tuberculosis therapy), viomycin (a second line drug for curing tuberculosis infection) and KKL-35 (a newly identified agent that can prevent growth of M. tuberculosis), have been shown to impair trans-translation in-vitro and in-vivo. Despite of intensive studies on the initiation and elongation phases of trans-translation, the mechanisms of the termination phase remain largely elusive. Our research background in ribosomal biology and structural biology was established during my postdoctoral and graduate studies. Base on our research foundation, our future research goals are to build on these finding using structural biology and biochemisty to address the following questions 1)what are the molecular mechanisms of termination process of trans-translation. 2) How does antimicrobial drug PZA and KKL-35 specifically bind to the ribosome and inhibit translation rescue. 3) How does viomycin inhibit translation rescue. It is anticipated that these studies will provide fundamental new concepts for understanding translation rescue in bacterium and for designing novel compounds that will effectively inhibit translation rescue which can potentially be used for curing infectious disease caused by pathogenic bacteria.