Every cell, whether eukaryotic or prokaryotic, has mechanisms to control and dispose of their protein waste. Damaged proteins, or any protein not needed at a specific time, are tagged, recognized and then degraded by (more or less) complex energy-dependent proteolytic machines. Chemical biologists have learned to hijack proteolysis to eliminate disease-causing proteins from the cell. This is achieved by small molecules known as PROTACs and molecular glues, which can simultaneously engage a component of the cellular protein degradation system and the protein targeted for degradation. By promising to drug the undruggable, PROTACs and glues have encouraged considerable investments in the pharmaceutical sector. From the outset, the focus was on human cells and cancer chemotherapy, while bacteria and antibiotic discovery were left behind.

Back in 2016, this thought had been on my mind for a while, when I attended a seminar by Tim Clausen and read his paper a few months later, reporting that phosphorylation marks proteins for degradation in Bacillus subtilis. One of the reasons why targeted protein degradation had not been translated to bacteria is that bacterial protein degradation pathways are remarkably different from human cells. In 2016, Trentini, Suskiewicz et al. discovered a unique protein degradation pathway in bacteria, where the underlying concept resembled the post-translational tagging for degradation seen in the ubiquitin–proteasome system of eukaryotic cells. Specifically, substrate tagging with a phosphate group was followed by degradation by an energy-dependent proteolytic complex, ClpCP, present in Gram-positive bacteria and mycobacteria. Also, it did not involve serine, threonine or tyrosine phosphorylation, but instead arginine, making it even more interesting.