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

ABSTRACT: Antimicrobial resistance is a global health threat that requires the development of new treatment concepts. These should not only overcome existing resistance but be designed to slow down the 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 are extending this concept by developing 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 are derived from cyclomarins which, when dimerized, generate compounds that recruit and degrade ClpC1. The resulting Homo-BacPROTACs reduce levels of endogenou

SUBMITTER: Junk L 

PROVIDER: S-EPMC10914731 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature