Genome-wide gene expression tuning reveals diverse vulnerabilities of M. tuberculosis.
Cell
; 184(17): 4579-4592.e24, 2021 08 19.
Article
in En
| MEDLINE
| ID: mdl-34297925
ABSTRACT
Antibacterial agents target the products of essential genes but rarely achieve complete target inhibition. Thus, the all-or-none definition of essentiality afforded by traditional genetic approaches fails to discern the most attractive bacterial targets those whose incomplete inhibition results in major fitness costs. In contrast, gene "vulnerability" is a continuous, quantifiable trait that relates the magnitude of gene inhibition to the effect on bacterial fitness. We developed a CRISPR interference-based functional genomics method to systematically titrate gene expression in Mycobacterium tuberculosis (Mtb) and monitor fitness outcomes. We identified highly vulnerable genes in various processes, including novel targets unexplored for drug discovery. Equally important, we identified invulnerable essential genes, potentially explaining failed drug discovery efforts. Comparison of vulnerability between the reference and a hypervirulent Mtb isolate revealed incomplete conservation of vulnerability and that differential vulnerability can predict differential antibacterial susceptibility. Our results quantitatively redefine essential bacterial processes and identify high-value targets for drug development.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Gene Expression Regulation, Bacterial
/
Genome, Bacterial
/
Mycobacterium tuberculosis
Type of study:
Prognostic_studies
Language:
En
Journal:
Cell
Year:
2021
Document type:
Article
Affiliation country:
United States