Advancing phage therapy for human urinary tract infections

This project is one of 17 four year PhD Studentships funded by Medical Research Scotland (MRS) (https://www.medicalresearchscotland.org.uk) to be delivered jointly by the named University and External Partner Organisation (EPO). The Studentship will provide the first-class academic and additional training provided by the EPO needed to equip the successful candidate for a science career in an increasingly competitive market.

"Advancing phage therapy for human urinary tract infections" to be delivered by the University of Edinburgh [Supervisors: Professor David Gally (Division of Infection and Immunity, Roslin Institute, University of Edinburgh) and Dr Gavin Paterson (Royal (Dick) School of Veterinary Medicine and the Roslin Institute, University of Edinburgh)] and Proteon Pharmaceuticals (https://www.proteonpharma.com) [External Partner Organisation supervisor: Dr Ewelina Wojcik].

Urinary tract infections (UTIs) are common, sometimes recurrent and can lead to life-threatening systemic infections. Human UTIs are often associated with E. coli which originate from the gastrointestinal tract. E. coli is an important cause of blood-borne infections and about half of these originate from UTIs. Research into bacteriophage (phage) therapy has been re-gaining traction due to the urgent need to develop alternatives to antimicrobials and counter the growing global threat of antimicrobial resistance. Phage therapy offers an alternative to antibiotic treatment as phage can specifically infect and kill bacteria. UTIs are a good candidate infection for phage therapy as the phage can be directly delivered to the infection site. Phage are a natural product and need to be cultured using bacterial ‘production’ strains; as such the preparations need extensive purification to remove inflammatory factors like endotoxin. This PhD will focus on the need to have diverse phage produced from a safe detoxified E. coli strain background that has been modified to allow infection by the majority of phage in our growing collection.

There will be three aspects to this MRS studentship: (1) to identify novel phage infection mechanisms, mainly focused on phage receptors. We will interrogate our database of thousands of phage-E. coli interactions in order to mine E. coli sequences for novel phage receptors. Candidates will be cloned and tested in the detoxified E. coli background produced in part 2. (2) Detoxification of the Lipid A component of LPS in a manner similar to that applied for ClearColi©. Our focus will be to reduce the capacity of Lipid A to activate TLR4 inflammation. You will also study LPS changes that may expand the phage infection spectrum of the strain. (3) The efficacy and inflammatory capacity of selected phage cocktails produced in the production strains will be tested against a new panel of sequenced human UTI isolates in pooled human urine and/or an in vitro bladder model. Training will be provided in both bioinformatics and laboratory skills required for the research. 

The project would suit someone interested in phage therapy and who wants to become a real expert in genetic manipulation of E. coli. As well as the molecular biology the project would involve tissue culture, bioinformatics, protein and LPS work. We have a commercial partner, Proteon Pharmaceuticals, for the project who aim to apply the strains for commercial production of phage.

ENQUIRIES:

Enquiries should be sent by email to Professor David Gally:

[Email Address Removed]

APPLICATIONS:

Applicants must have obtained, or expect to obtain, a first or 2.1 UK honours degree and/or an MSc, or equivalent for degrees obtained outside the UK, in a relevant subject.

Applications are welcome from UK nationals as well as EU nationals that hold UK settled or pre-settled status.

Applicants should send a CV, the contact details of 2 referees (including postal and email addresses) and a covering letter explaining why they would be suited to this project, by email to:

[Email Address Removed]

When applying for the studentship please state clearly the project title and the supervisor in your covering letter.

Please note, your application may be shared with the funders of this PhD Studentship, Medical Research Scotland and Proteon Pharmaceuticals.

Interviews are expected to take place approximately 2-3 weeks after the closing date for applications. Interviews may be conducted by video conference.

It is anticipated that the PhD Studentship will start 3 October 2022.