Enabling antibiotics discovery by targeted protein degradation

A 2025 Crick PhD project with Ester Morreale.

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

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.[2] 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.[2] 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.