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MRC DTP: Delivery and mode of action of novel antimicrobial toxins


School of Life Sciences

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Dr S Coulthurst , Prof W N Hunter No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

Many bacterial pathogens use the Type VI secretion system (T6SS) nanomachine to fire diverse toxic ‘effector’ proteins directly into target cells. The T6SS plays a key role in the virulence and competitiveness of diverse Gram-negative bacteria, including important human pathogens. Whilst in some cases the T6SS can be used to directly attack host cells, as a classical virulence factor, the primary role of the T6SS is believed to be during inter-bacterial competition, when bacteria use the T6SS to deliver anti-bacterial effectors into other bacterial cells, killing or inhibiting their rivals. Additionally, we have recently discovered that bacteria can also use T6SS-delivered effectors against microbial fungi, including important fungal pathogens. Anti-microbial T6SSs thus provide a competitive mechanism to allow pathogens to proliferate in polymicrobial infection sites or environmental reservoirs and ultimately cause disease. Understanding T6SS-mediated effector delivery and the lethal consequences of these effectors on targeted cells therefore offers the potential to uncover new ways to kill or inhibit bacterial and fungal pathogens.

In the Coulthurst group, we study the roles of the T6SS, the mechanisms of effector delivery, and the nature and mode-of-action of T6SS-dependent effector proteins. We utilise a wide range of molecular and cellular approaches and focus on representative examples of Gram-negative bacterial pathogens. In this project, the mechanism of action and delivery of one or more newly-identified T6SS effector proteins will be investigated. In an inter-disciplinary study, we will combine, as required, molecular microbiology, genetics, ‘omics and cell biology approaches (SJC) with structural and biochemical analysis (WNH) and advanced microscopy and image analysis (CR). We aim to uncover the mode of action of the toxin, its journey of recognition and delivery by the T6SS and the consequences for the targeted cell. The student will gain experience in a number of state-of-the-art molecular techniques as well as a strong grounding in microbiology and molecular biology and opportunities to engage with the international research community and the general public.




References


Recent work from the lab and an overview of the research area can be found in the following references:

Mariano, G., Trunk, K., Williams, D.J., Monlezun, L., Strahl, H., Pitt, S.J. & Coulthurst, S.J. (2019). A family of Type VI secretion system effector proteins that form ion-selective pores. Nature Communications, 10, 5484.

Trunk, K., Peltier, J., Liu, Y., Dill, B.D., Walker, L., Gow, N.A.R., Stark, M.J.R., Quinn, J., Strahl, H., Trost, M. & Coulthurst, S.J. (2018) The Type VI secretion system deploys anti-fungal effectors against microbial competitors. Nature Microbiology, 3, 920–931.

Coulthurst, S.J. (2019) The Type VI secretion system: a versatile bacterial weapon. Microbiology, 165, 503–515.


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