2. Academic Validation
  3. BacPROTACs mediate targeted protein degradation in bacteria

BacPROTACs mediate targeted protein degradation in bacteria

  • Cell. 2022 Jun 23;185(13):2338-2353.e18. doi: 10.1016/j.cell.2022.05.009.
Francesca E Morreale 1,  Stefan Kleine 2,  Julia Leodolter 1,  Sabryna Junker 1,  David M Hoi 1,  Stepan Ovchinnikov 1,  Anastasia Okun 1,  Juliane Kley 1,  Robert Kurzbauer 1,  Lukas Junk 3,  Somraj Guha 3,  David Podlesainski 2,  Uli Kazmaier 3,  Guido Boehmelt 4,  Harald Weinstabl 4,  Klaus Rumpel 4,  Volker M Schmiedel 4,  Markus Hartl 5,  David Haselbach 1,  Anton Meinhart 1,  Markus Kaiser 6,  Tim Clausen 7
Affiliations

Affiliations

  • 1 Research Institute of Molecular Pathology, Vienna Biocenter, 1030 Vienna, Austria.
  • 2 University of Duisburg-Essen, Center of Medical Biotechnology, Faculty of Biology, 45141 Essen, Germany.
  • 3 Saarland University, Organic Chemistry I, 66123 Saarbrücken, Germany.
  • 4 Boehringer Ingelheim RCV GmbH & Co KG, 1120 Vienna, Austria.
  • 5 Max Perutz Laboratories, Vienna Biocenter, 1030 Vienna, Austria.
  • 6 University of Duisburg-Essen, Center of Medical Biotechnology, Faculty of Biology, 45141 Essen, Germany. Electronic address: markus.kaiser@uni-due.de.
  • 7 Research Institute of Molecular Pathology, Vienna Biocenter, 1030 Vienna, Austria; Medical University of Vienna, 1030 Vienna, Austria. Electronic address: tim.clausen@imp.ac.at.
PMID: 35662409 DOI: 10.1016/j.cell.2022.05.009
Abstract

Hijacking the cellular protein degradation system offers unique opportunities for drug discovery, as exemplified by proteolysis-targeting chimeras. Despite their great promise for medical chemistry, so far, it has not been possible to reprogram the Bacterial degradation machinery to interfere with microbial infections. Here, we develop small-molecule degraders, so-called BacPROTACs, that bind to the substrate receptor 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. The induced higher-order oligomer was visualized by cryo-EM analysis, providing a structural snapshot of activated ClpC unfolding a protein substrate. Finally, drug susceptibility and degradation assays performed in mycobacteria demonstrate in vivo activity of BacPROTACs, allowing selective targeting of endogenous proteins via fusion to an established degron. In addition to guiding Antibiotic discovery, the BacPROTAC technology presents a versatile research tool enabling the inducible degradation of Bacterial proteins.

Keywords

AAA proteases; antimicrobials; bacterial PROTACs; targeted protein degradation.

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