Design, synthesis and screening of inhibitors of Pseudomonas Aeruginosa

Pseudomonas aeruginosa often presents as a multi-drug resistant gram-negative opportunistic pathogen responsible for chronic lung colonisation in cystic fibrosis patients and many other acute infections (Qin et al, 2022). There is an urgent need for new drug therapies against new molecular targets in this organism. This project will focus on a heretofore unexploited target in the pathogen, namely the enzyme transglutaminase (Uruburu et al, 2019), which is responsible for protein crosslinking, and without which the organism is unviable.

In preparation, at Aston, several potential inhibitors of the enzyme have been identified by means of protein-ligand molecular dynamics simulations. The project will continue with such simulations to enlarge the pool of potential inhibitors. These will be prepared by chemical synthesis and screened for inhibition of recombinantly-expressed and purified Pseudomonas transglutaminase, and if successful, for the ability to inhibit planktonic and biofilm growth of the organism. The biological test results will inform successive rounds of inhibitor optimisation. Fluorescent inhibitors will also be included with a view to probing the localisation of the inhibitor within the organism and, concomitantly, the cellular localisation of the active transglutaminase, which is postulated to be periplasmic.

References

• Uruburu et al, Journal of Structural Biology, 2019, 205, 18-25 (https://doi.org/10.1016/j.jsb.2018.12.004)

Qin et al, Sig Transduct Target Ther, 2022, 7, 199 (https://doi.org/10.1038/s41392-022-01056-1

Supervisors

Dan Rathbone, Chemistry Lead

Russell Collighan, Biology Lead

PhD programmes are for those who are seeking to develop greater in-depth knowledge in a specific area. Completing this level of study is about making an original contribution to knowledge, making new discoveries and developing lifelong skills. 

At Aston University, our Engineering and Physical Sciences PhD programmes will provide all the support and facilities you will need to develop into a leading researcher in your chosen field.  You will be welcomed into a supportive community with a shared enthusiasm for original research, where diversity and multidisciplinary is championed.

Person Specification

Candidates should have been awarded, or expect to achieve, EITHER:

• A Bachelors degree in a relevant subject with an award of First Class or 2.1. 

OR 

• A Bachelors degree in a relevant subject with an award of First Class or 2.1, and a Masters degree in a relevant subject with an award of Merit or higher.

Qualifications from other countries which are considered by Aston University to be equivalent to that described above will be eligible to apply.

Submitting an application

We can only consider applications that are complete and have all supporting documents. Applications that do not provide all the relevant documents will be automatically rejected. Your application must include: 

1. English language copies of the transcripts and certificates for all your higher education degrees, including any Bachelor's degrees.
    
2. A Research Statement detailing your understanding of the research area, how you would approach the project, and a brief review of relevant literature. Be sure to use the title of the research project you are applying for. There is no set format or word count. 
    
3. A personal statement which outlines any further information which you think is relevant to your application, such as your personal suitability for research, career aspirations, possible future research interests, and further description of relevant employment experience. 
    
4. Two academic referees who can discuss your suitability for independent research. References must be on headed paper, signed, and dated no more than 2 years old. At least one reference should be from your most recent University. You can submit your references at a later date if necessary. 
    
5. Evidence that you meet the English Language requirements. If you do not currently meet the language requirements, you can submit this at a later stage. 
    
6. A copy of your passport. Where relevant, include evidence of settled or pre-settled status.

Interviews

Interviews will be conducted online via Microsoft Teams. If you are shortlisted, you will be contacted directly with details of the interview.  

Studying a PhD is great route into academia and industries that are centred on research and innovation. Areas with a demand for very high level and specialised research skills often demand PhDs.

In addition to this specialist knowledge, PhD education will help you to develop a set of valuable transferrable skills. The very nature of studying an intensive research degree will enable you to become a team player, develop problem-solving skills, analytical thinking, and advanced presentation and communication skills.

The variety of PhD project topics at Aston means that the destinations of our graduates vary substantially. Some choose to continue into academia, at either Aston or other leading institutions, while others go onto use their newly acquired skills in a range of research, healthcare, industry or charitable fields. When selecting your chosen PhD path at Aston, your supervisor will be able to provide you with relevant career opportunities that could be available to you in your specialist area.