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The ClpC1:ClpP1:ClpP2 (ClpC1P1P2) protease plays an essential role in maintaining protein homeostasis and counteracting host-induced stresses, and it therefore represents a promising Mycobacterium tuberculosis (Mtb) drug target. The antimicrobial cyclic peptides cyclomarin A and ecumicin target ClpC1, binding to overlapping sites on the ClpC1 N-terminal domain (ClpC1NTD) and impairing ClpC1 activity by mechanisms that remain unclear. Using quantitative proteomics, Hoi et al. find these agents to cause large proteome imbalances, including upregulation of two stress response factors, ClpC2 and ClpC3. These proteins use the same ligand-binding sites as those present in ClpC1 to compete for substrate binding and can sequester ClpC1-directed antibiotics, thus reducing their cytotoxicity. To overcome this protection and to target Clp degradation, Hoi et al. harness the recently developed BacPROTAC technology, which relies on bi-functional chemical adapters that bind to a protein of interest (POI) and to the ClpC1NTD substrate receptor, thereby targeting POIs to the Clp protease and inducing their degradation. Their BacPROTAC, comprised of two linked cyclomarin A heads, directed ClpC1 against itself, inducing its elimination by the ClpC1P1P2 protease, as well as promoting degradation of ClpC2. In cell culture, the BacPROTAC impaired growth of a highly virulent Mtb strain, with 115-fold higher potency than parent cyclomarin compounds.
