Exploring BacPROTACs as a new paradigm for antibacterial discovery

The modulation of "essential" or "vulnerable" protein targets through targeted protein degradation (TPD) offers an innovative alternative approach for the discovery of new antibacterials. We propose that the challenges currently associated with inhibitor-focused small molecule antibacterial drug discovery may be addressed by pivoting to the development of bacterial proteolysis targeting chimeras (BacPROTACs) as novel Gram-negative antibacterials that promote the reduction of target protein levels by selectively engaging the bacterial ClpP protease. This proposal is built on recent published studies that have shown TPD to be a viable strategy for anti-tuberculosis drug discovery, as well on our own unpublished successes in developing BacPROTACs that inhibit the growth of Mycobacterium tuberculosis with MIC values below 1 µM while showing no cytotoxicity against HepG2 cells at 100 µM. Specifically, we propose to show that small molecule BacPROTACs that activate the ClpP protease and accelerate the rate of degradation of selected, validated targets through a proximity effect will inhibit the growth of Klebsiella pneumoniae and Escherichia coli based on the unique pharmacology of these compounds. Moreover, we will demonstrate proof-of-concept that applying TPD to proteins that induce or support resistance to known antimicrobials may counter such resistance in clinical strains of these organisms.