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性生长抑制（CDI）系统介导的。CDI系统存在于多种革兰氏阴性细菌中，包括许多重要的人类病原体。CDI由双伴侣分泌蛋白的CdiB/CdiA家族介导。CdiB是Omp 85外膜蛋白，其是将CdiA外蛋白输出和组装到细胞表面上所需的。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）递送到靶细胞中。CDI系统还编码CdiI免疫蛋白，其特异性结合CdiA-CT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序列在细菌之间高度可变，相应的CdiI免疫蛋白也是如此。目前的分析表明，CDI系统编码至少120个不同的CDI毒素免疫家族。本申请提出了遗传、生物化学和超微结构分析的组合，以获得对CDI期间细胞-细胞相互作用和CdiA-CT毒素递送的机制见解。这项研究将大大 增加我们对细菌病原体的生态学和进化的理解，并可以为抗菌治疗提供新的方法。

 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.