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

细菌已经进化出复杂的策略来相互竞争和交流。一个重要的问题 细菌间竞争的机制是由接触依赖生长抑制(CDI)系统介导的。 CDI系统广泛存在于各种革兰氏阴性细菌中，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是一个Omp85 CDIA效应蛋白出口和组装到细胞上所需的外膜蛋白 浮出水面。CDIA与易感细菌上的受体结合，然后递送其C末端毒素结构域(CDIA- Ct)进入目标单元。CDI系统还编码CDI免疫蛋白，与CDIA-CT和 中和毒素活性，保护CDI+细胞免受自身抑制。值得注意的是，CDIA-CT序列 细菌之间是可变的，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。这个应用程序提出了一种组合 遗传、生化和超微结构分析，以获得对细胞-细胞相互作用的机械性见解和 CDIA-CT毒素在CDI中的传递。这项研究将大大增加我们对生态的理解 和细菌病原体的进化，并可能为抗菌治疗的新方法提供信息。

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 CdiA effector proteins 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 bind the CdiA-CT and neutralize toxin activity to protect 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.