Abstract
The autoinducer (AI) that initiates the quorum sensing (QS) signaling cascade in Pseudomonas aeruginosa is an acyl-homoserine lactone (acyl-HSL). We initiated a study of the requirements for binding of the AI to its protein effector LasR by synthesizing a library of analogs with the HSL moiety replaced with different amines and alcohols. We tested each compound for both agonist and antagonist activity using a QS-controlled reporter gene assay and found several new agonists and antagonists. A representative antagonist was further tested for its ability to inhibit virulence factors. This data progresses our understanding of the LasR-AI interaction toward the rational design of therapeutic inhibitors of QS.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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4-Butyrolactone / analogs & derivatives*
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4-Butyrolactone / chemical synthesis
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4-Butyrolactone / pharmacology
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Aminophenols / chemistry
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Bacterial Proteins
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Biofilms / drug effects
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Biofilms / growth & development
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / metabolism*
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Drug Design
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Gene Library*
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Genes, Reporter / drug effects
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Genetic Techniques
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Homoserine / agonists
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Homoserine / analogs & derivatives*
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Homoserine / antagonists & inhibitors
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Homoserine / chemical synthesis
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Homoserine / genetics
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Homoserine / metabolism*
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Homoserine / pharmacology
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Lactones / agonists
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Lactones / antagonists & inhibitors
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Lactones / metabolism*
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Molecular Structure
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Pseudomonas aeruginosa / metabolism
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Pseudomonas aeruginosa / pathogenicity*
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Quinolones / pharmacology
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Signal Transduction / drug effects
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Structure-Activity Relationship
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Trans-Activators / chemistry
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Trans-Activators / metabolism*
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Virulence Factors / biosynthesis
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Virulence Factors / genetics
Substances
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2-heptyl-3-hydroxy-4-quinolone
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Aminophenols
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Bacterial Proteins
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DNA-Binding Proteins
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Lactones
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LasR protein, Pseudomonas aeruginosa
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N-(3-oxododecanoyl)homoserine lactone
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N-butyrylhomoserine lactone
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Quinolones
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Trans-Activators
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Virulence Factors
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Pseudomonas aeruginosa autoinducer
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2-aminophenol
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Homoserine
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4-Butyrolactone