Abstract
The pathogenic bacterium Pseudomonas aeruginosa uses acyl-homoserine lactone quorum-sensing signals to coordinate the expression of a battery of virulence genes in a cascade of regulatory events. The quorum-sensing signal that triggers the cascade is N-3-oxo-dodecanoyl homoserine lactone (3OC12-HSL), which interacts with two signal receptor-transcription factors, LasR and QscR. This signal is base labile, and it is degraded by mammalian PON lactonases. We have identified a structurally unrelated triphenyl mimic of 3OC12-HSL that is base-insensitive and PON-resistant. The triphenyl mimic seems to interact specifically with LasR but not with QscR. In silico analysis suggests that the mimic fits into the 3OC12-HSL-binding site of LasR and makes key contacts with LasR. The triphenyl mimic is an excellent scaffold for developing quorum-sensing inhibitors, and its stability and potency make it ideal for biotechnology uses such as heterologous gene expression.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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4-Butyrolactone / analogs & derivatives*
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4-Butyrolactone / chemistry
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4-Butyrolactone / metabolism
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Bacterial Proteins / chemistry
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Bacterial Proteins / metabolism
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / metabolism
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Escherichia coli / genetics
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Escherichia coli / metabolism
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Homoserine / analogs & derivatives*
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Homoserine / chemistry
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Homoserine / metabolism
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Models, Molecular
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Molecular Mimicry
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Molecular Structure
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Pseudomonas aeruginosa / genetics
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Pseudomonas aeruginosa / metabolism*
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Pseudomonas aeruginosa / pathogenicity
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Quorum Sensing / physiology*
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Repressor Proteins / chemistry
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Repressor Proteins / metabolism
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Signal Transduction
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Trans-Activators / chemistry
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Trans-Activators / metabolism
Substances
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Bacterial Proteins
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DNA-Binding Proteins
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LasR protein, Pseudomonas aeruginosa
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N-(3-oxododecanoyl)homoserine lactone
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QscR protein, Pseudomonas aeruginosa
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Repressor Proteins
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Trans-Activators
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Homoserine
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4-Butyrolactone