Secretion, mode of action and utilisation of a new anti-bacterial toxin

蛋白质分泌系统在病原菌的毒力、宿主相互作用和竞争生存中起着重要作用。它们是专门的机器，用于将特定蛋白质从细菌细胞中转移到环境中或直接注射到靶细胞中。一个广泛的和相对最近确定的例子是VI型分泌系统（T6SS）。越来越明显的是，这种T6SS在多种革兰氏阴性菌的毒力和竞争力中起着关键作用，包括重要的人类、动物和植物病原体。病原体可以使用T6SS直接靶向真核生物，作为经典的毒力因子。或者，许多病原体可以使用T6SS靶向其他细菌细胞，杀死或抑制竞争对手。因此，“抗菌”T6SS提供了一种竞争机制，允许病原体在多微生物感染部位或环境储库中增殖，并最终导致疾病。抗菌T6SS将有毒蛋白质递送到目标细菌细胞中，有效地杀死它们或抑制它们的生长。最近在该领域的工作，包括我们实验室的工作，表明不同的T6SS分泌多种多样的新型抗菌毒素。虽然迄今为止已经对几大类毒素进行了功能性表征，特别是附着在细菌细胞壁或细胞膜上的酶毒素，但许多其他毒素似乎与已知蛋白质无关。我们已经鉴定了新的T6SS分泌的抗菌毒素，其不属于任何先前描述的类别。因此，它们在易感细胞中的作用模式和细胞靶点是未知的。这个博士项目的重点将是研究这些新毒素之一，以确定其毒性模式，分泌途径，易感细胞中的细胞靶点以及毒素发挥作用所需的靶细胞的任何细胞功能。如何自我抵抗或'免疫'的分泌细胞中的毒素是实现，也将检查相关毒素在不同的生物体中的分布。重要的是发现新的抗菌毒素的脆弱的细胞靶点，因为它们可能揭示抗生素或其他药物设计的新靶点。毒素也可能是了解基本细菌生理学或具有生物技术效用的有价值的研究工具。

Protein secretion systems play a central role in the virulence, host interaction and competitive survival of bacterial pathogens. They are specialised machines used to translocate specific proteins out of the bacterial cell, either to the environment or injected directly into target cells. A widespread and relatively recently-identified example is the Type VI secretion system (T6SS). It is becoming increasingly apparent that this T6SS plays a key role in the virulence and competitiveness of diverse Gram-negative bacteria, including important human, animal and plant pathogens. Pathogens can use T6SSs to directly target eukaryotic organisms, as classical virulence factors. Alternatively, many pathogens can use T6SSs to target other bacterial cells, killing or inhibiting rivals. 'Anti-bacterial' T6SSs thus provide a competitive mechanism to allow pathogens to proliferate in polymicrobial infection sites or environmental reservoirs and ultimately cause disease. Anti-bacterial T6SSs deliver toxic proteins into target bacterial cells, efficiently killing them or inhibiting their growth. Recent work in the field, including from our lab, suggests that different T6SSs secrete multiple, diverse and novel anti-bacterial toxins. Whilst several broad classes have been functionally characterised to date, particularly enzymic toxins attaching the bacterial cell wall or cell membrane, many other toxins appear unrelated to known proteins. We have identified new T6SS-secreted anti-bacterial toxins which do not fall into any of the previously described classes. Therefore their mode of action and cellular target in susceptible cells is unknown. The focus of this PhD project will be to study one of these new toxins in order to determine its mode of toxicity, pathway of secretion, cellular target in susceptible cells and any cellular functions of the target cell which are required in order for the toxin to exert its effect. How self-resistance or 'immunity' to the toxin in the secreting cell is achieved will also be examined, as will the distribution of related toxins in different organisms. It is important to discover the vulnerable cellular targets of new anti-bacterial toxins since they may reveal new targets for antibiotic or other drug design. The toxins may also represent valuable research tools to understand basic bacterial physiology or have biotechnological utility.