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

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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.