University of Dundee

BacPROTACs mediate targeted protein degradation in bacteria.

Event Date: 
Friday, August 26, 2022 - 12:00 to 13:00
Event Location: 
MSI Small Lecture Theatre
Host: 
Professor Alessio Ciulli FRSC
Event Speaker: 
Dr Ester Morreale
Institution: 
Research Institute of Molecular Pathology, Vienna
Event Type: 
Seminar
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The Centre for Targeted Protein Degradation

in conjunction with the

Division of Molecular Microbiology

and the

MRC Protein Phosphorylation and Ubiquitylation Unit

 

Spotlight Seminar

 

Abstract

Hijacking the cellular protein degradation system offers unique opportunities for drug discovery, as exemplified by proteolysis-targeting chimeras. Despite their great promise, it has so far not been possible to reprogram the bacterial degradation machinery to interfere with microbial infections. In our study, we develop small-molecule degraders, so-called BacPROTACs, that bind to the substrate receptor domain of the ClpC:ClpP protease, priming neo-substrates for degradation. In addition to their targeting function, BacPROTACs activate ClpC, transforming the resting unfoldase into its functional state, as visualized by cryo-EM analysis. Finally, drug susceptibility and degradation assays performed in mycobacteria demonstrate cellular activity of BacPROTACs, enabling conditional knockdowns of endogenous bacterial proteins fused to a developed degron. BacPROTAC technology represents a versatile research tool allowing the inducible degradation of bacterial proteins and paves the way to a novel antibiotic development modality.