Molecular Mechanisms of anti-bacterial contact-dependent growth inhibition (CDI)

 描述(由申请人提供)：细菌已经进化出复杂的策略来相互竞争和交流。细菌间竞争的一个重要机制是由接触依赖的生长抑制(CDI)系统介导的。CDI系统广泛存在于各种革兰氏阴性菌中，包括许多重要的人类病原体。CDI是由CDIB/CDIA家族的两个伙伴分泌蛋白介导的。CDIB是一种Omp85外膜蛋白，是CDIA外源蛋白输出和组装到细胞表面所必需的。CDIA与易感细菌上的受体结合，然后将其C末端毒素结构域(CDIA-CT)传递到靶细胞。CDI系统还编码CDI免疫蛋白，这些蛋白与CDIA-CT特异性结合并中和毒素活性，从而保护CDI细胞免受自身抑制。值得注意的是，CDIA-CT序列在细菌之间差异很大，相应的CdiI免疫蛋白也是如此。目前的分析表明，CDI系统至少编码120个不同的CDI毒素免疫家族。这项应用提出了遗传、生化和超微结构分析的组合，以获得对CDI过程中细胞-细胞相互作用和CDIA-CT毒素传递的机械性见解。这项研究将具有重要的意义 增加我们对细菌病原体的生态学和进化的理解，并可能为抗菌治疗的新方法提供信息。

 DESCRIPTION (provided by applicant): Bacteria have evolved complex strategies to compete and communicate with one another. One important mechanism of inter-bacterial competition is mediated by contact-dependent growth inhibition (CDI) systems. CDI systems are found in a wide variety of Gram-negative bacteria, including many important human pathogens. CDI is mediated by the CdiB/CdiA family of two-partner secretion proteins. CdiB is an Omp85 outer-membrane protein that is required for the export and assembly of the CdiA exoprotein onto the cell surface. CdiA binds to receptors on susceptible bacteria and then delivers its C-terminal toxin domain (CdiA- CT) into the target cell. CDI systems also encode CdiI immunity proteins, which specifically bind to the CdiA- CT and neutralize toxin activity, thereby protecting CDI+ cells from auto-inhibition. Remarkably, CdiA-CT sequences are highly variable between bacteria, as are the corresponding CdiI immunity proteins. Current analysis indicates that CDI systems encode at least 120 distinct CDI toxin-immunity families. This application proposes a combination of genetic, biochemical and ultrastructural analyses to gain mechanistic insights into cell-cell interactions and CdiA-CT toxin delivery during CDI. This research will significantly increase our understanding of the ecology and evolution of bacterial pathogens and could inform novel approaches to antimicrobial therapy.