Potent modulation of the CepR quorum sensing receptor and virulence in a Burkholderia cepacia complex member using non-native lactone ligands

The Burkholderia cepacia complex (Bcc) is a family of closely related bacterial pathogens that are the causative agent of deadly human infections. Virulence in Bcc species has been shown to be controlled by the CepI/CepR quorum sensing (QS) system, which is mediated by an N -acyl L-homoserine lacton...

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Veröffentlicht in:Scientific reports 2019-09, Vol.9 (1), p.13449-12, Article 13449
Hauptverfasser: Slinger, Betty L., Deay, Jacqueline J., Chandler, Josephine R., Blackwell, Helen E.
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description The Burkholderia cepacia complex (Bcc) is a family of closely related bacterial pathogens that are the causative agent of deadly human infections. Virulence in Bcc species has been shown to be controlled by the CepI/CepR quorum sensing (QS) system, which is mediated by an N -acyl L-homoserine lactone (AHL) signal (C 8 -AHL) and its cognate LuxR-type receptor (CepR). Chemical strategies to block QS in Bcc members would represent an approach to intercept this bacterial communication process and further delineate its role in infection. In the current study, we sought to identify non-native AHLs capable of agonizing or antagonizing CepR, and thereby QS, in a Bcc member. We screened a library of AHL analogs in cell-based reporters for CepR, and identified numerous highly potent CepR agonists and antagonists. These compounds remain active in a Bcc member, B . multivorans , with one agonist 250-fold more potent than the native ligand C 8 -AHL, and can affect QS-controlled motility. Further, the CepR antagonists prolong C . elegans survival in an infection model. These AHL analogs are the first reported non-native molecules that both directly modulate CepR and impact QS-controlled phenotypes in a Bcc member, and represent valuable chemical tools to assess the role of QS in Bcc infections.
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subjects 13/95
38/39
38/47
631/326/421
631/92/96
64/11
Acyl-Butyrolactones - metabolism
Agonists
Animals
Antibiotics
Bacteria
Bacterial Proteins - agonists
Bacterial Proteins - antagonists & inhibitors
Bacterial Proteins - genetics
Bacterial Proteins - metabolism
beta-Galactosidase - genetics
Binding sites
Biofilms
Burkholderia cepacia
Burkholderia cepacia complex - drug effects
Burkholderia cepacia complex - pathogenicity
Burkholderia Infections - microbiology
Caenorhabditis elegans - drug effects
Chemical communication
Cystic fibrosis
Drug Evaluation, Preclinical
Escherichia coli - genetics
Gene expression
Genes, Reporter
Homoserine lactones
Humanities and Social Sciences
Infections
Laboratories
Ligands
Motility
multidisciplinary
Pathogens
Phenotypes
Quorum sensing
Quorum Sensing - drug effects
Quorum Sensing - physiology
Science
Science (multidisciplinary)
Virulence
title Potent modulation of the CepR quorum sensing receptor and virulence in a Burkholderia cepacia complex member using non-native lactone ligands
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