c-di-AMP signaling plays important role in determining antibiotic tolerance phenotypes of Mycobacterium smegmatis.
Sci Rep
; 12(1): 13127, 2022 07 30.
Article
em En
| MEDLINE
| ID: mdl-35907936
ABSTRACT
In this study, we probe the role of secondary messenger c-di-AMP in drug tolerance, which includes both persister and resistant mutant characterization of Mycobacterium smegmatis. Specifically, with the use of c-di-AMP null and overproducing mutants, we showed how c-di-AMP plays a significant role in resistance mutagenesis against antibiotics with different mechanisms of action. We elucidated the specific molecular mechanism linking the elevated intracellular c-di-AMP level and high mutant generation and highlighted the significance of non-homology-based DNA repair. Further investigation enabled us to identify the unique mutational landscape of target and non-target mutation categories linked to intracellular c-di-AMP levels. Overall fitness cost of unique target mutations was estimated in different strain backgrounds, and then we showed the critical role of c-di-AMP in driving epistatic interactions between resistance genes, resulting in the evolution of multi-drug tolerance. Finally, we identified the role of c-di-AMP in persister cells regrowth and mutant enrichment upon cessation of antibiotic treatment.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Mycobacterium smegmatis
/
Antibacterianos
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article