Targeted Protein Degradation in bacteria?

Applications of Bacterial Degrons and Degraders - Toward Targeted Protein Degradation in Bacteria.

Izert MA, Klimecka MM, Górna MW

Front Mol Biosci 8:669762 (2021) https://doi.org/10.3389/fmolb.2021.669762

In our review article, we shared our thoughts on the prospects of various flavours of Targeted Protein Degradation in bacteria. Bacterial degraders could be designed based on naturally occuring degrons that would recruit the proteolytic machinery. These could be ligands of post-translationally modifying enzymes, adaptor proteins, unfoldases or even peptidases that participate in the most robust degradation pathways in bacteria.

strategies for targeted protein degradation in bacteria based on: (A) induced degron exposure e.g. by Pyrazinamide, (B) PROTACs recruiting PafA (C) OR arginine kinase, (D) PROTACs directly binding an adaptor, an unfoldase, or a peptidase. Made with BioRender.com.

EDIT:

Excitingly, the first report that followed our publication indicates that this approach might indeed be viable in bacteria. BacPROTACs containing pArg degron or CymA ligand were successful in recruiting the ClpC or ClpC1 to degrade neo-substrates or fusion proteins. ClpC is present in Gram-positive bacteria and ClpC1 in mycobacteria, and these unfoldases may be exploited by future degrader antibiotics acting against pathogens from these phyla.