Overview
Antimicrobial resistance (AMR) is a major global health threat, with Acinetobacter baumannii among the most concerning multidrug-resistant pathogens. This opportunistic bacterium causes severe hospital-acquired infections and is listed by the WHO as a “critical priority” pathogen1. With treatment options increasingly limited, new strategies to combat infection are urgently needed.
About this opportunity
This project takes an alternative approach by targeting bacterial virulence rather than survival, aiming to disarm the pathogen without promoting antibiotic resistance2. The focus is on carboxy-terminal processing proteases (CTPs), a conserved family of serine proteases that regulate cell envelope integrity, signalling, and virulence across all domains of life. Intriguingly, A. baumannii possesses an uncharacterised CTP, which is linked to virulence3, but its molecular function remains unknown.
Research Aims:
This PhD project will uncover how CTPs contribute to A. baumannii virulence and explore their potential as novel therapeutic targets4. The student will define the functional role of the A. baumannii CTP by identifying its interacting proteins and substrates through advanced proteomic approaches, and by evaluating CTP mutants in infection models. Mechanistic studies will focus on how proteolysis is regulated and what determines substrate selectivity, by employing biochemical, biophysical, and structural biology techniques. Peptide-based inhibitors will then be developed and assessed as mechanistic probes to define CTP function and evaluate their impact on pathogen fitness and virulence.
Techniques & Training:
The successful candidate will join an ambitious and supportive research group, dedicated to uncover the molecular mechanisms that underpin bacterial virulence and drive the development of anti-virulence strategies. The project offers exceptional multidisciplinary training across molecular microbiology, infection biology, and structural biochemistry, providing a versatile skillset highly valued in both academia and biotechnology. You will be based in the Department of Clinical Infection, Microbiology & Immunology at the University of Liverpool, benefiting from access to outstanding facilities, technical support, and a vibrant scientific community.
You will receive advanced, hands-on training in cutting-edge methodologies, including:
- Molecular biology: Core experience in cloning, recombinant protein expression, and purification, forming the foundation for downstream structural and functional studies.
- Structural biology: Application of X-ray crystallography to resolve the enzyme structures and ligand-bound states, advancing understanding of molecular mechanisms and guiding inhibitor design.
- Biochemistry & biophysics: Enzyme kinetics, site-directed mutagenesis, and biophysical interaction assays to dissect enzyme activity, regulation, and substrate specificity.
- Infection biology: Microbial assays and clinically relevant in vivo infection models to assess the physiological role of CTPs and their contribution to virulence.
- Proteomics & bioinformatics: Quantitative and targeted proteomic approaches to identify enzyme substrates and map protein–protein interaction networks.
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of-the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, training opportunities or internships in science policy, science communication and beyond.
Further information on the programme and instructions on how to apply, including a link to the application portal, can be found on our website https://www.dimen.org.uk/
Further reading
1. Morris, F. C., Dexter, C., Kostoulias, X., Uddin, M. I. & Peleg, A. Y. The Mechanisms of Disease Caused by Acinetobacter baumannii. Frontiers in Microbiology 10, doi:10.3389/fmicb.2019.01601 (2019).
2. Lau, W. Y. V., Taylor, P. K., Brinkman, F. S. L. & Lee, A. H. Y. Pathogen-associated gene discovery workflows for novel antivirulence therapeutic development. EBioMedicine 88, 104429, doi:10.1016/j.ebiom.2022.104429 (2023).
3. Roy, R., You, R.-I., Lin, M.-D. & Lin, N.-T. Mutation of the Carboxy-Terminal Processing Protease in Acinetobacter baumannii Affects Motility, Leads to Loss of Membrane Integrity, and Reduces Virulence. Pathogens 9, 322, doi:10.3390/pathogens9050322 (2020).
4. Harding, C. J., Bischoff, M., Bergkessel, M. & Czekster, C. M. An anti-biofilm cyclic peptide targets a secreted aminopeptidase from P. aeruginosa. Nature Chemical Biology 19, 1158-1166, doi:10.1038/s41589-023-01373-8 (2023).