Iron limitation in M. tuberculosis has broad impact on central carbon metabolism.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
09 07 2022
09 07 2022
Historique:
received:
15
02
2022
accepted:
28
06
2022
entrez:
9
7
2022
pubmed:
10
7
2022
medline:
14
7
2022
Statut:
epublish
Résumé
Mycobacterium tuberculosis (Mtb), the cause of the human pulmonary disease tuberculosis (TB), contributes to approximately 1.5 million deaths every year. Prior work has established that lipids are actively catabolized by Mtb in vivo and fulfill major roles in Mtb physiology and pathogenesis. We conducted a high-throughput screen to identify inhibitors of Mtb survival in its host macrophage. One of the hit compounds identified in this screen, sAEL057, demonstrates highest activity on Mtb growth in conditions where cholesterol was the primary carbon source. Transcriptional and functional data indicate that sAEL057 limits Mtb's access to iron by acting as an iron chelator. Furthermore, pharmacological and genetic inhibition of iron acquisition results in dysregulation of cholesterol catabolism, revealing a previously unappreciated linkage between these pathways. Characterization of sAEL057's mode of action argues that Mtb's metabolic regulation reveals vulnerabilities in those pathways that impact central carbon metabolism.
Identifiants
pubmed: 35810253
doi: 10.1038/s42003-022-03650-z
pii: 10.1038/s42003-022-03650-z
pmc: PMC9271047
doi:
Substances chimiques
Carbon
7440-44-0
Cholesterol
97C5T2UQ7J
Iron
E1UOL152H7
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
685Subventions
Organisme : NIAID NIH HHS
ID : R01 AI134183
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI155319
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
ID : AI134183
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
ID : AI155319
Informations de copyright
© 2022. The Author(s).
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