PhD Studentship: Controlling Clostridioides difficile infections through phage therapy (MED1995)

Supervisors: Professor Nigel P Minton, Dr Klaus Winzer, Dr Sarah Kuehne

Clostridioides difficile (C. diff) is a serious, worldwide, public health threat. The leading infective cause of hospital-acquired and antibiotic-associated diarrhoea, every year around half a million new cases of C. difficile infection (CDI) occur in the US and Europe.   Management in the US is estimated to cost $6.3 billion per year and over £120 million of additional annual costs to the UK NHS.  Although, current antibiotics can treat mild cases, they are less effective at managing recurrent or severe CDI.  More worrying, antibiotic-resistant isolates of C. diff are becoming more prevalent.  Alternative therapies are urgently required and phage therapy holds considerable promise. 

Used to treat and prevent infectious disease long before antibiotics, bacteriophage cause no collateral damage to normal microbiota as they are inherently non-toxic and highly specific to their intended target. Their use is particularly attractive, as C. diff is restricted to the gastrointestinal tract, simplifying phage delivery and avoiding potential problems of immunogenicity associated with systemic infections. Until now, however, two issues have hindered its adoption. Firstly, classic therapy is reliant on obligate lytic phage and, to date, not a single such C. Diff phage has been reported, only temperate (lysogenic) bacteriophage. Secondly, those phage that have been isolated exhibit narrow specificity, infecting only a limited number of strains.  

Recent progress at Nottingham provide solutions to these impediments, a lytic phage has been isolated and we have developed proprietary CRISPR/Cas genome editing tools that allow modification of phage genomes.  Excitingly, we used these tools to swap phage genes involved in C. diff recognition and binding thereby changing phage specificity from one hypervirulent strain to another. These same tools enabled enhancement of the therapeutic potential of temperate phage through the addition of lethal cargo.   Combining these breakthroughs, the prospect of developing cocktails of synthetic C. diff phages active against the prevalent outbreak strains is feasible.  

The PhD’s goal is to capitalize on these breakthroughs in phage isolation and characterization through the design, build and test of synthetic bacteriophage cocktails effective against those dominant C. diff strains responsible for CDI.  Two ‘platforms’ will be pursued: (i) a lytic platform based on our newly isolated phage, and; (ii) a lysogenic platform incorporating elements designed to kill the host upon lysogeny. The project will involve anaerobic microbiology, DNA synthesis, cloning, synthetic biology, CRISPR/Cas genome editing, electron/high resolution microscopy, bioinformatics, in vivo testing, receptor biology, therapeutics and biochemistry.

The three year studentship covers tuition fees and a tax-free stipend, UK Students only.

At least a 2.1 Honours degree in Microbiology, Biochemistry or related field.

Informal inquiries to nigel.minton@nottingham.ac.uk 

Application details: to apply for this PhD opportunity, please submit the following documents to nigel.minton@nottingham.ac.uk

Closing Date: 31 Mar 2024
Category: Studentships