Discovery of inhibitors of Pseudomonas aeruginosa virulence through the search for natural-like compounds with a dual role as inducers and substrates of efflux pumps.
Journal
Environmental microbiology
ISSN: 1462-2920
Titre abrégé: Environ Microbiol
Pays: England
ID NLM: 100883692
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
revised:
25
03
2021
received:
15
01
2021
accepted:
03
04
2021
pubmed:
6
4
2021
medline:
18
3
2022
entrez:
5
4
2021
Statut:
ppublish
Résumé
Multidrug efflux pumps are ancient elements encoded in every genome, from bacteria to humans. In bacteria, in addition to antibiotics, efflux pumps extrude a wide range of substrates, including quorum sensing signals, bacterial metabolites, or plant-produced compounds. This indicates that their original functions may differ from their recently acquired role in the extrusion of antibiotics during human infection. Concerning plant-produced compounds, some of them are substrates and inducers of the same efflux pump, suggesting a coordinated plant/bacteria coevolution. Herein we analyse the ability of 1243 compounds from a Natural Product-Like library to induce the expression of P. aeruginosa mexCD-oprJ or mexAB-oprM efflux pumps' encoding genes. We further characterized natural-like compounds that do not trigger antibiotic resistance in P. aeruginosa and that act as virulence inhibitors, choosing those that were not only inducers but substrates of the same efflux pump. Four compounds impair swarming motility, exotoxin secretion through the Type 3 Secretion System (T3SS) and the ability to kill Caenorhabditis elegans, which might be explained by the downregulation of genes encoding flagellum and T3SS. Our results emphasize the possibility of discovering new anti-virulence drugs by screening natural or natural-like libraries for compounds that behave as both, inducers and substrates of efflux pumps.
Identifiants
pubmed: 33818002
doi: 10.1111/1462-2920.15511
doi:
Substances chimiques
Anti-Bacterial Agents
0
Bacterial Outer Membrane Proteins
0
Bacterial Proteins
0
Membrane Transport Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7396-7411Informations de copyright
© 2021 Society for Applied Microbiology and John Wiley & Sons Ltd.
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