Mechanism of phage infection in the C. difficile pathogen- towards effective phage therapy

Increasing resistance to antibiotics is one of the greatest challenges facing humanity today. Clostridioides difficile is the primary cause of antibiotic-associated infections in UK hospitals and antibiotic-induced disruption of the gut microbiota is a prerequisite for infection. Current treatments rely on a small number of antibiotics but these cause further damage to the microbiota and relapse is common. There is an urgent need for species specific therapeutics that can kill C. difficile while sparing the beneficial species of the gut microbiota. Bacteriophage are a promising solution to this tricky problem.

Phage are efficient and specific killers of C. difficile which could be further refined through guided genetic engineering. We have developed a streamlined CryoEM pipeline for the structural and mechanistic analysis of phage and have already solved the near atomic resolution structures of two complete contractile phages and one phage tail-like particle that kill C. difficile. We have also shown that the S-layer is the major receptor for the majority of C. difficile phage and have solved the structure of this cell surface structure. In this project we aim to use cutting edge imaging techniques and the insights gained from our structural analyses to study the interaction between the phage and a live cell that leads to successful infection and death of the host cell, at unprecedented resolution.

You will receive training in advanced techniques including super-resolution light microscopy, atomic force microscopy and cryo-electron tomography, supported by three dynamic research groups with a long-established and successful history of collaboration over 11 years, four jointly supervised PhD students and three joint postdoctoral scientists.