BacPROTAC-induced protein degradation as a new antibiotic concept.

Antibiotic resistance is spreading worldwide, associated with more than 5 million deaths annually, yet few new antibiotics have emerged in recent years. This gap highlights the need for alternative strategies that enable the rational design of antibacterial agents. One promising approach is the development of proteolysis-targeting chimeras in bacteria (BacPROTACs), which can hijack endogenous degradation pathways. BacPROTACs tether selected proteins to caseinolytic proteases (Clp) to promote their degradation. Thus, unlike conventional inhibitors, they eliminate their targets, act in a catalytic manner, and can exploit weak binders. Furthermore, BacPROTACs have been shown to reach pathogens in infected cells, exhibiting potent activity against multidrug-resistant Mycobacterium tuberculosis. While challenges remain in cell entry, substrate selectivity, and pharmacokinetic optimization, BacPROTACs offer a promising route to develop next-generation antibiotics.