CinA mediates multidrug tolerance in Mycobacterium tuberculosis.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
22 04 2022
22 04 2022
Historique:
received:
01
12
2020
accepted:
31
03
2022
entrez:
23
4
2022
pubmed:
24
4
2022
medline:
27
4
2022
Statut:
epublish
Résumé
The ability of Mycobacterium tuberculosis (Mtb) to resist and tolerate antibiotics complicates the development of improved tuberculosis (TB) chemotherapies. Here we define the Mtb protein CinA as a major determinant of drug tolerance and as a potential target to shorten TB chemotherapy. By reducing the fraction of drug-tolerant persisters, genetic inactivation of cinA accelerated killing of Mtb by four antibiotics in clinical use: isoniazid, ethionamide, delamanid and pretomanid. Mtb ΔcinA was killed rapidly in conditions known to impede the efficacy of isoniazid, such as during nutrient starvation, during persistence in a caseum mimetic, in activated macrophages and during chronic mouse infection. Deletion of CinA also increased in vivo killing of Mtb by BPaL, a combination of pretomanid, bedaquiline and linezolid that is used to treat highly drug-resistant TB. Genetic and drug metabolism studies suggest that CinA mediates drug tolerance via cleavage of NAD-drug adducts.
Identifiants
pubmed: 35459278
doi: 10.1038/s41467-022-29832-1
pii: 10.1038/s41467-022-29832-1
pmc: PMC9033802
doi:
Substances chimiques
Antitubercular Agents
0
Isoniazid
V83O1VOZ8L
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2203Subventions
Organisme : NIAID NIH HHS
ID : R25 AI140472
Pays : United States
Informations de copyright
© 2022. The Author(s).
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