Two-Way Regulation of MmpL3 Expression Identifies and Validates Inhibitors of MmpL3 Function in Mycobacterium tuberculosis.
ACS Infect Dis
; 7(1): 141-152, 2021 01 08.
Article
em En
| MEDLINE
| ID: mdl-33319550
ABSTRACT
MmpL3, an essential mycolate transporter in the inner membrane of Mycobacterium tuberculosis (Mtb), has been identified as a target of multiple, chemically diverse antitubercular drugs. However, several of these molecules seem to have secondary targets and inhibit bacterial growth by more than one mechanism. Here, we describe a cell-based assay that utilizes two-way regulation of MmpL3 expression to readily identify MmpL3-specific inhibitors. We successfully used this assay to identify a novel guanidine-based MmpL3 inhibitor from a library of 220 compounds that inhibit growth of Mtb by largely unknown mechanisms. We furthermore identified inhibitors of cytochrome bc1-aa3 oxidase as one class of off-target hits in whole-cell screens for MmpL3 inhibitors and report a novel sulfanylacetamide as a potential QcrB inhibitor.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Contexto em Saúde:
3_ND
Problema de saúde:
3_neglected_diseases
/
3_tuberculosis
Assunto principal:
Proteínas de Membrana Transportadoras
/
Proteínas de Bactérias
/
Mycobacterium tuberculosis
Idioma:
En
Revista:
ACS Infect Dis
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos