Derailing the aspartate pathway of Mycobacterium tuberculosis to eradicate persistent infection.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
16 09 2019
16 09 2019
Historique:
received:
14
09
2018
accepted:
28
08
2019
entrez:
19
9
2019
pubmed:
19
9
2019
medline:
7
1
2020
Statut:
epublish
Résumé
A major constraint for developing new anti-tuberculosis drugs is the limited number of validated targets that allow eradication of persistent infections. Here, we uncover a vulnerable component of Mycobacterium tuberculosis (Mtb) persistence metabolism, the aspartate pathway. Rapid death of threonine and homoserine auxotrophs points to a distinct susceptibility of Mtb to inhibition of this pathway. Combinatorial metabolomic and transcriptomic analysis reveals that inability to produce threonine leads to deregulation of aspartate kinase, causing flux imbalance and lysine and DAP accumulation. Mtb's adaptive response to this metabolic stress involves a relief valve-like mechanism combining lysine export and catabolism via aminoadipate. We present evidence that inhibition of the aspartate pathway at different branch-point enzymes leads to clearance of chronic infections. Together these findings demonstrate that the aspartate pathway in Mtb relies on a combination of metabolic control mechanisms, is required for persistence, and represents a target space for anti-tuberculosis drug development.
Identifiants
pubmed: 31527595
doi: 10.1038/s41467-019-12224-3
pii: 10.1038/s41467-019-12224-3
pmc: PMC6746716
doi:
Substances chimiques
Antitubercular Agents
0
Threonine
2ZD004190S
Aspartic Acid
30KYC7MIAI
Lysine
K3Z4F929H6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4215Subventions
Organisme : NIAID NIH HHS
ID : R37 AI026170
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI007501
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI026170
Pays : United States
Organisme : NIAID NIH HHS
ID : F30 AI138483
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007288
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI119573
Pays : United States
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