Immunosuppressive but non-LasR-inducing analogues of the pseudomonas aeruginosa quorum-sensing molecule N-(3-Oxododecanoyl)-l-homoserine Lactone

Gopal Jadhav, Siri Ram Chhabra, Gary Telford, Doreen S.W. Hooi, Karima Righetti, Paul Williams, Barrie Kellam, David I. Pritchard, Peter M. Fischer

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Figure Presented. 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 N1-(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.

Original languageEnglish (US)
Pages (from-to)3348-3359
Number of pages12
JournalJournal of Medicinal Chemistry
Volume54
Issue number9
DOIs
StatePublished - May 12 2011
Externally publishedYes

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Quorum Sensing
Immunosuppressive Agents
Pseudomonas aeruginosa
Immune System
Leukocytes
N-(3-oxododecanoyl)homoserine lactone
homoserine lactone

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Immunosuppressive but non-LasR-inducing analogues of the pseudomonas aeruginosa quorum-sensing molecule N-(3-Oxododecanoyl)-l-homoserine Lactone. / Jadhav, Gopal; Chhabra, Siri Ram; Telford, Gary; Hooi, Doreen S.W.; Righetti, Karima; Williams, Paul; Kellam, Barrie; Pritchard, David I.; Fischer, Peter M.

In: Journal of Medicinal Chemistry, Vol. 54, No. 9, 12.05.2011, p. 3348-3359.

Research output: Contribution to journalArticle

Jadhav, G, Chhabra, SR, Telford, G, Hooi, DSW, Righetti, K, Williams, P, Kellam, B, Pritchard, DI & Fischer, PM 2011, 'Immunosuppressive but non-LasR-inducing analogues of the pseudomonas aeruginosa quorum-sensing molecule N-(3-Oxododecanoyl)-l-homoserine Lactone', Journal of Medicinal Chemistry, vol. 54, no. 9, pp. 3348-3359. https://doi.org/10.1021/jm2001019
Jadhav, Gopal ; Chhabra, Siri Ram ; Telford, Gary ; Hooi, Doreen S.W. ; Righetti, Karima ; Williams, Paul ; Kellam, Barrie ; Pritchard, David I. ; Fischer, Peter M. / Immunosuppressive but non-LasR-inducing analogues of the pseudomonas aeruginosa quorum-sensing molecule N-(3-Oxododecanoyl)-l-homoserine Lactone. In: Journal of Medicinal Chemistry. 2011 ; Vol. 54, No. 9. pp. 3348-3359.
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abstract = "Figure Presented. 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 N1-(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.",
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