Inhibition of Pseudomonas aeruginosa quorum sensing by chemical induction of the MexEF-oprN efflux pump.

Autor:	Kristensen R; Department of Immunology and Microbiology, Costerton Biofilm Center, University of Copenhagen, Copenhagen, Denmark., Andersen JB; Department of Immunology and Microbiology, Costerton Biofilm Center, University of Copenhagen, Copenhagen, Denmark., Rybtke M; Department of Immunology and Microbiology, Costerton Biofilm Center, University of Copenhagen, Copenhagen, Denmark., Jansen CU; Department of Chemistry, Technical University of Denmark, Lyngby, Denmark., Fritz BG; Department of Immunology and Microbiology, Costerton Biofilm Center, University of Copenhagen, Copenhagen, Denmark., Kiilerich RO; Department of Immunology and Microbiology, Costerton Biofilm Center, University of Copenhagen, Copenhagen, Denmark., Uhd J; Department of Chemistry, Technical University of Denmark, Lyngby, Denmark., Bjarnsholt T; Department of Immunology and Microbiology, Costerton Biofilm Center, University of Copenhagen, Copenhagen, Denmark.; Department of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark., Qvortrup K; Department of Chemistry, Technical University of Denmark, Lyngby, Denmark., Tolker-Nielsen T; Department of Immunology and Microbiology, Costerton Biofilm Center, University of Copenhagen, Copenhagen, Denmark., Givskov M; Department of Immunology and Microbiology, Costerton Biofilm Center, University of Copenhagen, Copenhagen, Denmark., Jakobsen TH; Department of Immunology and Microbiology, Costerton Biofilm Center, University of Copenhagen, Copenhagen, Denmark.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2024 Feb 07; Vol. 68 (2), pp. e0138723. Date of Electronic Publication: 2024 Jan 08.
DOI:	10.1128/aac.01387-23
Abstrakt:	The cell-to-cell communication system quorum sensing (QS), used by various pathogenic bacteria to synchronize gene expression and increase host invasion potentials, is studied as a potential target for persistent infection control. To search for novel molecules targeting the QS system in the Gram-negative opportunistic pathogen Pseudomonas aeruginosa , a chemical library consisting of 3,280 small compounds from LifeArc was screened. A series of 10 conjugated phenones that have not previously been reported to target bacteria were identified as inhibitors of QS in P. aeruginosa . Two lead compounds (ethylthio enynone and propylthio enynone) were re-synthesized for verification of activity and further elucidation of the mode of action. The isomeric pure Z-ethylthio enynone was used for RNA sequencing, revealing a strong inhibitor of QS-regulated genes, and the QS-regulated virulence factors rhamnolipid and pyocyanin were significantly decreased by treatment with the compounds. A transposon mutagenesis screen performed in a newly constructed lasB-gfp monitor strain identified the target of Z-ethylthio enynone in P. aeruginosa to be the MexEF-OprN efflux pump, which was further established using defined mex knockout mutants. Our data indicate that the QS inhibitory capabilities of Z-ethylthio enynone were caused by the drainage of intracellular signal molecules as a response to chemical-induced stimulation of the MexEF-oprN efflux pump, thereby inhibiting the autogenerated positive feedback and its enhanced signal-molecule synthesis. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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