| Autor: |
Woods KE; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045., Akhter S; Center for Computational Biology, University of Kansas, Lawrence, KS 66045., Rodriguez B; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045., Townsend KA; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045., Smith N; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045., Smith B; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045., Wambua A; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045., Craddock V; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045., Abisado-Duque RG; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045., Santa EE; Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706., Manson DE; Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706., Oakley BR; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045., Hancock LE; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045., Miao Y; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045.; Center for Computational Biology, University of Kansas, Lawrence, KS 66045.; Current location: Department of Pharmacology and Computational Medicine Program, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599., Blackwell HE; Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706., Chandler JR; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045. |
| Abstrakt: |
Quorum sensing (QS) is a cell-cell signaling system that enables bacteria to coordinate population density-dependent changes in behavior. This chemical communication pathway is mediated by diffusible N -acyl L-homoserine lactone signals and cytoplasmic signal-responsive LuxR-type receptors in Gram-negative bacteria. As many common pathogenic bacteria use QS to regulate virulence, there is significant interest in disrupting QS as a potential therapeutic strategy. Prior studies have implicated the natural products salicylic acid, cinnamaldehyde and other related benzaldehyde derivatives as inhibitors of QS in the opportunistic pathogen Pseudomonas aeruginosa , yet we lack an understanding of the mechanisms by which these compounds function. Herein, we evaluate the activity of a set of benzaldehyde derivatives using heterologous reporters of the P. aeruginosa LasR and RhlR QS signal receptors. We find that most tested benzaldehyde derivatives can antagonize LasR or RhlR reporter activation at micromolar concentrations, although certain molecules also caused mild growth defects and nonspecific reporter antagonism. Notably, several compounds showed promising RhlR or LasR specific inhibitory activities over a range of concentrations below that causing toxicity. Ortho- Vanillin, a previously untested compound, was the most promising within this set. Competition experiments against the native ligands for LasR and RhlR revealed that ortho -vanillin can interact competitively with RhlR but not with LasR. Overall, these studies expand our understanding of benzaldehyde activities in the LasR and RhlR receptors and reveal potentially promising effects of ortho -vanillin as a small molecule QS modulator against RhlR. |
