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.