Discovery of natural-product-derived sequanamycins as potent oral anti-tuberculosis agents.
antibacterial
clarithromycin
drug discovery
emr37
erythromycin
macrolide
ribosome
sequanamycin
tuberculosis
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
02 03 2023
02 03 2023
Historique:
received:
02
04
2021
revised:
03
08
2022
accepted:
27
01
2023
pubmed:
25
2
2023
medline:
8
3
2023
entrez:
24
2
2023
Statut:
ppublish
Résumé
The emergence of drug-resistant tuberculosis has created an urgent need for new anti-tubercular agents. Here, we report the discovery of a series of macrolides called sequanamycins with outstanding in vitro and in vivo activity against Mycobacterium tuberculosis (Mtb). Sequanamycins are bacterial ribosome inhibitors that interact with the ribosome in a similar manner to classic macrolides like erythromycin and clarithromycin, but with binding characteristics that allow them to overcome the inherent macrolide resistance of Mtb. Structures of the ribosome with bound inhibitors were used to optimize sequanamycin to produce the advanced lead compound SEQ-9. SEQ-9 was efficacious in mouse models of acute and chronic TB as a single agent, and it demonstrated bactericidal activity in a murine TB infection model in combination with other TB drugs. These results support further investigation of this series as TB clinical candidates, with the potential for use in new regimens against drug-susceptible and drug-resistant TB.
Identifiants
pubmed: 36827973
pii: S0092-8674(23)00102-2
doi: 10.1016/j.cell.2023.01.043
pmc: PMC9994261
pii:
doi:
Substances chimiques
Antitubercular Agents
0
Macrolides
0
Clarithromycin
H1250JIK0A
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
1013-1025.e24Subventions
Organisme : NIAID NIH HHS
ID : P01 AI095208
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests Jidong Zhang, K.A., Y.B., N.B., F.B.-P., C.C., and A.R. are employed by Sanofi R&D. C.L., C.R., S. Sans, S. Silve, I.B., and S.L. were employed by Sanofi R&D and now Evotec. M.B.B. was employed by Sanofi R&D and now Inrae, France. L.F. was employed by Sanofi R&D and now Drugs for Neglected Diseases initiative (DNDi), Switzerland.
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