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 endogenous ClpC1 in Mycobacterium smegmatis and display minimum inhibitory concentrations in the low micro- to nanomolar range in mycobacterial strains, including multiple drug-resistant Mtb isolates. The compounds also kill Mtb residing in macrophages. Thus, Homo-BacPROTACs that degrade ClpC1 represent a different strategy for targeting Mtb and overcoming drug resistance.

Navigating Antibacterial Frontiers: A Panoramic Exploration of Antibacterial Landscapes, Resistance Mechanisms, and Emerging Therapeutic Strategies

“…In recent studies, scientists have developed BAC-PROTACs targeting M. tuberculosis. 420 This technology is in nascent stages and can be explored further for treating resistant bacterial infections. Role of Antisense Oligonucleotides.…”

“…Mechanistically, a bifunctional BAC-PROTAC targets caseinolytic protease complex (ClpC-ClpP) for specific protein degradation by binding to both the target protein and activating ClpC component. In recent studies, scientists have developed BAC-PROTACs targeting M. tuberculosis . This technology is in nascent stages and can be explored further for treating resistant bacterial infections.…”