IMB-BZ as an Inhibitor Targeting ESX-1 Secretion System to Control Mycobacterial Infection.
J Infect Dis
; 225(4): 608-616, 2022 02 15.
Article
en En
| MEDLINE
| ID: mdl-34558604
ABSTRACT
BACKGROUND:
Resistance to anti-tuberculosis (TB) drugs is a major issue in TB control, and demands the discovery of new drugs targeting the virulence factor ESX-1.METHODS:
We first established a high-throughput screen (HTS) assay for the discovery of ESX-1 secretion inhibitors. The positive hits were then evaluated for the potency of diminishing the survival of virulent mycobacteria and reducing bacterial virulence. We further investigated the probability of inducing drug resistance and the underlying mechanism using mycobacterial protein fragment complementation.RESULTS:
A robust HTS assay was developed to identify small molecules that inhibit ESX-1 secretion without impairing bacterial growth in vitro. A hit named IMB-BZ specifically inhibits the secretion of CFP-10 and reduces virulence in an ESX-1-dependent manner, therefore resulting in significant reduction in intracellular and in vivo survival of mycobacteria. Blocking the CFP-10-EccCb1 interaction directly or indirectly underlies the inhibitory effect of IMB-BZ on the secretion of CFP-10. Importantly, our finding shows that the ESX-1 inhibitors pose low risk of drug resistance development by mycobacteria in vitro as compared with traditional anti-TB drugs, and exhibit high potency against chronic mycobacterial infection.CONCLUSIONS:
Targeting ESX-1 may lead to the development of novel therapeutics for tuberculosis. IMB-BZ holds the potential for future development into a new anti-TB drug.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Tuberculosis
/
Sistemas de Secreción Tipo VII
/
Mycobacterium tuberculosis
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Infect Dis
Año:
2022
Tipo del documento:
Article
País de afiliación:
China