Abstract
The Pseudomonas aeruginosa quorum-sensing molecule N-(3-oxododecanoyl)-l-homoserine lactone (1) is involved not only in bacterial activation but also in subversion of the host immune system, and this compound might thus be used as a template to design immunosuppressive agents, provided derivatives devoid of quorum-sensing activity could be discovered. By use of a leukocyte proliferation assay and a newly developed bioluminescent P. aeruginosa reporter assay, systematic modification of 1 allowed us to delineate the bacterial LasR-induction and host immunosuppressive activities. The main determinant is replacement of the methylene group proximal to the β-ketoamide in the acyl chain of 1 with functions containing heteroatoms, especially an NH group. This modification can be combined with replacement of the homoserine lactone system in 1 with stable cyclic groups. For example, we found the simple compound N(1)-(5-chloro-2-hydroxyphenyl)-N(3)-octylmalonamide (25d) to be over twice as potent as 1 as an immune suppressor while displaying LasR-induction antagonist activity.
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 / chemistry
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4-Butyrolactone / pharmacology
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Animals
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Aza Compounds / chemical synthesis
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Aza Compounds / chemistry
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Aza Compounds / pharmacology
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Bacterial Proteins / biosynthesis*
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Bacterial Proteins / genetics
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Cell Proliferation / drug effects
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Homoserine / analogs & derivatives*
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Homoserine / chemical synthesis
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Homoserine / chemistry
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Homoserine / pharmacology
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Humans
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Immunosuppressive Agents / chemical synthesis*
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Immunosuppressive Agents / chemistry
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Immunosuppressive Agents / pharmacology
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Jurkat Cells
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Leukocytes / cytology
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Leukocytes / drug effects
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Luminescent Measurements
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Mice
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Pseudomonas aeruginosa / genetics
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Pseudomonas aeruginosa / physiology*
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Quorum Sensing*
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Structure-Activity Relationship
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Trans-Activators / biosynthesis*
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Trans-Activators / genetics
Substances
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Aza Compounds
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Bacterial Proteins
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Immunosuppressive Agents
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LasR protein, Pseudomonas aeruginosa
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N-(3-oxododecanoyl)homoserine lactone
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Trans-Activators
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Homoserine
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4-Butyrolactone