Homo-BacPROTAC-induced degradation of ClpC1 as a strategy against drug-resistant mycobacteria.
Nat Commun
; 15(1): 2005, 2024 Mar 05.
Article
em En
| MEDLINE
| ID: mdl-38443338
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Mycobacterium smegmatis
/
Mycobacterium tuberculosis
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article