About the Project
A 2027 Crick PhD project with Ester Morreale.
Project background and description
Our lab aims to establish targeted protein degradation (TPD) technology in pathogenic bacteria, addressing the critical need for novel antibiotic development strategies. TPD technology relies on eliminating target proteins from the cell using small molecule degraders, rather than temporarily inhibiting them with conventional inhibitors.
While TPD is now well established in human cells [1], its application to bacteria remains limited owing to fundamental differences in protein degradation pathways between eukaryotic and prokaryotic cells. Among bacterial pathogens, TPD is most advanced in Mycobacterium tuberculosis [2, 3], where degraders known as BacPROTACs have been designed to reprogramme the ClpC1P1P2 proteolytic complex. BacPROTACs are bifunctional small molecules comprising a ClpC1-binding ligand connected to a substrate-binding ligand that recruits target substrates to the proteolytic complex for targeted degradation. Beyond M. tuberculosis, the diversity of proteolytic complexes and degradation pathways across bacterial species poses a significant challenge, requiring pathogen-specific TPD strategies.
This PhD project aims to establish innovative strategies for inducing targeted protein degradation in pathogenic bacteria. You will design novel antibiotic degraders and investigate their mechanism of action combining biochemistry, biophysics, proteomics and molecular microbiology. As a PhD student in our lab, you will have the opportunity to lead your own project, acquire new experimental skills and work with a multidisciplinary and collaborative research team.
Candidate background
We welcome applications from motivated and enthusiastic candidates, eager to learn new techniques and work within an international, interdisciplinary team. This project is well suited to those with an interest in integrating biochemistry, biophysics, proteomics and molecular microbiology to develop novel targeted protein degradation strategies against pathogenic bacteria. Candidates should have a background in at least one of the following: molecular biology, biochemistry, chemical biology, structural biology, or microbiology, and be willing to acquire new skills throughout the project.
Lab-specific question
Tell us about an inspiring paper you have read (not from the lab you are applying to), and what made it stand out to you.
Funding Notes
Successful applicants will be awarded a non-taxable annual stipend of £27,715 plus payment of university tuition fees. Students of all nationalities are eligible to apply.
References
1. Faust, T.B., Donovan, K.A., Yue, H., Chamberlain, P.P. and Fischer, E.S. (2021) Small-Molecule Approaches to Targeted Protein Degradation. Annual Review of Cancer Biology 5: 181–201.
2. Morreale, F.E., Kleine, S., Leodolter, J., Junker, S., Hoi, D.M., Ovchinnikov, S., . . . Clausen, T. (2022) BacPROTACs mediate targeted protein degradation in bacteria. Cell 185: 2338–2353 e2318.
3. Brown, D.A., Davies, J.J., Fecht, S., Zhang, Y., Kunzelmann, S., Kent, L., . . . Morreale, F.E. (2026) Preprint: BacPROTACs outperform inhibitors in Mycobacterium tuberculosis. Available at: bioRxiv.