Homo-BacPROTAC-induced degradation of ClpC1 as a strategy against drug-resistant mycobacteria

Antimicrobial resistance is a global health threat that requires development of new treatment concepts. These should not only overcome existing resistance, but be designed to slow down emergence of new resistance mechanisms. Targeted protein degradation, whereby a drug redirects cellular proteolytic machinery towards degrading a specific target, is an emerging concept in drug discovery. We developed proteolysis targeting chimeras active in bacteria (BacPROTACs) that bind to ClpC1, a component of the mycobacterial protein degradation machinery. The anti-Mycobacterium tuberculosis (Mtb) BacPROTACs were derived from cyclomarins, natural products known to bind to ClpC1, which were dimerized resulting in compounds that recruit and degrade ClpC1. The resulting Homo-BacPROTACs reduced levels of endogenous ClpC1 in Mycobacterium smegmatis, as well as displayed minimum inhibitory concentrations in the low micro- to nanomolar range in mycobacterial strains, including multiple drug resistant Mtb isolates. The compounds also killed Mtb resident in macrophages. Thus, Homo-BacPROTACs that degrade ClpC1 represent a different strategy for targeting Mtb and overcoming drug resistance.