Combining CRISPRi and metabolomics for functional annotation of compound libraries.
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
05 2022
05 2022
Historique:
received:
17
02
2021
accepted:
05
01
2022
pubmed:
24
2
2022
medline:
3
5
2022
entrez:
23
2
2022
Statut:
ppublish
Résumé
Molecular profiling of small molecules offers invaluable insights into the function of compounds and allows for hypothesis generation about small-molecule direct targets and secondary effects. However, current profiling methods are limited in either the number of measurable parameters or throughput. Here we developed a multiplexed, unbiased framework that, by linking genetic to drug-induced changes in nearly a thousand metabolites, allows for high-throughput functional annotation of compound libraries in Escherichia coli. First, we generated a reference map of metabolic changes from CRISPR interference (CRISPRi) with 352 genes in all major essential biological processes. Next, on the basis of the comparison of genetic changes with 1,342 drug-induced metabolic changes, we made de novo predictions of compound functionality and revealed antibacterials with unconventional modes of action (MoAs). We show that our framework, combining dynamic gene silencing with metabolomics, can be adapted as a general strategy for comprehensive high-throughput analysis of compound functionality from bacteria to human cell lines.
Identifiants
pubmed: 35194207
doi: 10.1038/s41589-022-00970-3
pii: 10.1038/s41589-022-00970-3
pmc: PMC7612681
mid: EMS140722
doi:
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
482-491Subventions
Organisme : European Research Council
ID : 866004
Pays : International
Organisme : NIAID NIH HHS
ID : R01 AI139465
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI133191
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : ErratumIn
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
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