Anticytolytic screen identifies inhibitors of mycobacterial virulence protein secretion.
Cell Host Microbe
; 16(4): 538-48, 2014 Oct 08.
Article
en En
| MEDLINE
| ID: mdl-25299337
ABSTRACT
Mycobacterium tuberculosis (Mtb) requires protein secretion systems like ESX-1 for intracellular survival and virulence. The major virulence determinant and ESX-1 substrate, EsxA, arrests phagosome maturation and lyses cell membranes, resulting in tissue damage and necrosis that promotes pathogen spread. To identify inhibitors of Mtb protein secretion, we developed a fibroblast survival assay exploiting this phenotype and selected molecules that protect host cells from Mtb-induced lysis without being bactericidal in vitro. Hit compounds blocked EsxA secretion and promoted phagosome maturation in macrophages, thus reducing bacterial loads. Target identification studies led to the discovery of BTP15, a benzothiophene inhibitor of the histidine kinase MprB that indirectly regulates ESX-1, and BBH7, a benzyloxybenzylidene-hydrazine compound. BBH7 affects Mtb metal-ion homeostasis and revealed zinc stress as an activating signal for EsxA secretion. This screening approach extends the target spectrum of small molecule libraries and will help tackle the mounting problem of antibiotic-resistant mycobacteria.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Proteínas Bacterianas
/
Factores de Virulencia
/
Evaluación Preclínica de Medicamentos
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Fibroblastos
/
Antibacterianos
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Mycobacterium tuberculosis
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Cell Host Microbe
Asunto de la revista:
MICROBIOLOGIA
Año:
2014
Tipo del documento:
Article
País de afiliación:
Alemania