Identification and characterisation of the phage and host receptors in Clostridium difficile, a prerequisite for future phage therapies.

Clostridium difficile is the leading infective cause of hospital-acquired and antibiotic-associated diarrhoea with over 500,000 and 400,000 annual new cases of C. difficile infection (CDI) in the US and Europe, respectively. The cost of CDI management is considerable and those few antibiotics currently used to treat infections are compromised by increasing reports of antimicrobial resistant C. difficile isolates. Alternative therapies are required.

One particularly promising strategy is phage therapy. Numerous C. difficile phages have been isolated, but to date they are all temperate. Whilst this rules out conventional phage therapy (lytic phage required), such lysogenic phage are ideal for strategies that deliver a lethal cargo, such as a CRISPR/Cas9 array targeted against the lysogenized host. Oral delivery to the microbiome of a modified phage carrying a CRISPR array directed against a toxin gene, for instance, would eliminate all susceptible C. difficile strains.

An impediment to this approach is the narrow host range of C. difficile phages isolated to date. Whilst this could be overcome by rational engineering to broaden phage host range, little is known of the identity of either phage or host cell receptors. Gathering this information is the objective of this PhD project.

The outcome of this project will be the derivation of the identity of the phage and host cell receptor for up to four phage and a greater understanding of the nature of their interaction. The data will lay the foundation for the subsequent engineering of phage to broaden their host range and increase their therapeutic potential.