Immunosuppressive but non-LasR-inducing analogues of the Pseudomonas aeruginosa quorum-sensing molecule N-(3-oxododecanoyl)-l-homoserine lactone.
J Med Chem
; 54(9): 3348-59, 2011 May 12.
Article
em En
| MEDLINE
| ID: mdl-21488685
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 ß-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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pseudomonas aeruginosa
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Proteínas de Bactérias
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4-Butirolactona
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Transativadores
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Percepção de Quorum
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Homosserina
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Imunossupressores
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article