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 细菌间竞争的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细菌。 病原体CDI由双伴侣分泌蛋白的CdiB-CdiA家族介导。CDIB是Omp 85 CdiA效应蛋白输出和组装到细胞上所需的外膜蛋白 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-C）。 CT）进入靶细胞。CDI系统还编码CdiI免疫蛋白，其结合CdiA-CT， 中和毒素活性以保护CDI+细胞免受自身抑制。值得注意的是，CdiA-CT序列高度 在细菌之间是可变的，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种不同的CDI毒素免疫家族。本申请提出了一种组合 遗传，生化和超微结构分析，以获得细胞间相互作用的机制见解， CDI期间的CdiA-CT毒素递送。这项研究将大大增加我们对生态学的理解 和细菌病原体的进化，并可能为抗菌治疗提供新的方法。

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.