Low-cost anti-mycobacterial drug discovery using engineered E. coli.
Nat Commun
; 13(1): 3905, 2022 07 07.
Article
em En
| MEDLINE
| ID: mdl-35798732
ABSTRACT
Whole-cell screening for Mycobacterium tuberculosis (Mtb) inhibitors is complicated by the pathogen's slow growth and biocontainment requirements. Here we present a synthetic biology framework for assaying Mtb drug targets in engineered E. coli. We construct Target Essential Surrogate E. coli (TESEC) in which an essential metabolic enzyme is deleted and replaced with an Mtb-derived functional analog, linking bacterial growth to the activity of the target enzyme. High throughput screening of a TESEC model for Mtb alanine racemase (Alr) revealed benazepril as a targeted inhibitor, a result validated in whole-cell Mtb. In vitro biochemical assays indicated a noncompetitive mechanism unlike that of clinical Alr inhibitors. We establish the scalability of TESEC for drug discovery by characterizing TESEC strains for four additional targets.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Alanina Racemase
/
Mycobacterium tuberculosis
Tipo de estudo:
Health_economic_evaluation
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article