Morreale Lab | Enabling antibiotics discovery by targeted protein degradation

A 2023 Crick PhD project with Francesca Ester Morreale. This application is open until 12:00 noon on 22 March 2023.
Deadline for applications has passed.

Key information

Applications closed
22 March 2023, 12:00 GMT
Posted 08 February 2023

Research topics

Biochemistry & Proteomics Chemical Biology & High Throughput Infectious Disease Structural Biology & Biophysics
Background texture taken from the lab imagery.

A 2023 Crick PhD project with Francesca Ester Morreale.

Project background and description

In response to the critical need of novel antibiotic development approaches, our lab aims at establishing targeted protein degradation (TPD) technology in pathogenic bacteria. TPD technology [1] relies on eliminating target proteins from the cell through small molecule degraders, rather than temporarily inhibiting them with conventional inhibitors.                       

Degraders function by inducing proximity between target proteins and the cellular protein degradation machinery, normally controlling protein quality and turnover. Protein degradation pathways of eukaryotic and prokaryotic cells are significantly different. As an example, the ubiquitin proteasome system, responsible for protein quality control in human cells, is absent in bacteria. A conceptually similar protein degradation pathway in Gram positive bacteria uses arginine phosphorylation as a degradation tag for substrate proteolysis through ClpCP,[2] a proteolytic complex functionally related to the proteasome. Because of these remarkable differences between eukaryotic and prokaryotic cells, TPD approaches need to be tailored to each cellular system.

TPD technology is now well established in human cells,[1] while application to bacteria has remained largely unexplored. Laying the foundations for technology transfer to bacteria, a proof-of-concept study has shown that rationally designed small molecule degraders, named BacPROTACs, can induce elimination of model proteins by reprogramming the ClpCP proteolytic complex.[3] ClpCP-directed BacPROTACs are bifunctional small molecules composed of a ClpC-binding ligand connected to a substrate-recruiting moiety, bringing target substrates to the proteolytic complex. Besides their degradation-inducing function, BacPROTACs enabled trapping and visualisation of an active state of B. subtilis ClpC in the process of unfolding a client protein by cryo-EM, revealing a previously unknown activation mechanism.[3] While this study showed, for the first time, that TPD is also feasible in bacteria, the potentials of TPD technology to boost antibiotics discovery are just beginning to be explored.

The current PhD project aims at establishing innovative strategies to induce targeted protein degradation in pathogenic bacteria. You will investigate the mechanism of action of novel types of antibiotic degraders combining biochemistry, structural biology, proteomics and high-throughput screening. As a PhD student in our lab, you will have the opportunity to lead your project, acquire new experimental skills and interact with a multidisciplinary and collaborative research team.

Candidate background

We welcome applications from talented and enthusiastic candidates, curious and passionate about science, willing to learn new techniques and eager to interact with an international interdisciplinary team. This project would suit applicants interested in integrating biochemistry, structural biology, high-throughput screening and proteomics to establish novel targeted protein degradation strategies for pathogenic bacteria.

Experimental skills can be acquired in the lab, however previous experience in one (or more) of the following will be advantageous: molecular biology, biochemistry, chemical biology, structural biology, proteomics and microbiology.



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.         Trentini, D.B., Suskiewicz, M.J., Heuck, A., Kurzbauer, R., Deszcz, L., Mechtler, K. and Clausen, T. (2016)

            Arginine phosphorylation marks proteins for degradation by a Clp protease.

            Nature 539: 48-53. PubMed abstract

3.         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. PubMed abstract