Enabling antibiotics discovery by targeted protein degradation

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Targeted protein degradation technology offers unique opportunities for basic research and drug discovery. Yet application in bacteria has remained unexplored, due to the lack of a ubiquitin-proteasome system in prokaryotic cells. A recent study (Morreale FE et al. Cell, 2022) has now translated the concept to bacteria by hijacking ClpCP proteolytic complexes, essential for protein quality control in Gram-positives and mycobacteria. On this basis, we aim to expand the scope of targeted protein degradation modalities in bacteria, identifying novel antibiotics that harness different bacterial proteolytic complexes to degrade bacteria's own essential proteins.