Details

Autor(en) / Beteiligte

• Kristensen, Rasmus
• Andersen, Jens Bo
• Rybtke, Morten
• Jansen, Charlotte Uldahl
• Fritz, Blaine Gabriel
• Kiilerich, Rikke Overgaard
• Uhd, Jesper
• Bjarnsholt, Thomas
• Qvortrup, Katrine
• Tolker-Nielsen, Tim
• Givskov, Michael
• Jakobsen, Tim Holm

Titel

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

Ist Teil von

• Antimicrobial agents and chemotherapy, 2024-02, Vol.68 (2), p.e0138723

Ort / Verlag

United States

Erscheinungsjahr

2024

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 , 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 . 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 monitor strain identified the target of Z-ethylthio enynone in to be the MexEF-OprN efflux pump, which was further established using defined 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.