title: Immunosuppressive but non-LasR-inducing analogues of the Pseudomonas aeruginosa quorum-sensing molecule N-(3-oxododecanoyl)-l-homoserine lactone.
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.
authors.affiliation: School of Pharmacy, University of Nottingham, University Park, Nottingham, NG7 2RD, U.K.
authors.forename: Gopal P
authors.initials: GP
authors.lastname: Jadhav
authors.forename: Siri Ram
authors.initials: SR
authors.lastname: Chhabra
authors.forename: Gary
authors.initials: G
authors.lastname: Telford
authors.forename: Doreen S W
authors.initials: DS
authors.lastname: Hooi
authors.forename: Karima
authors.initials: K
authors.lastname: Righetti
authors.forename: Paul
authors.initials: P
authors.lastname: Williams
authors.forename: Barrie
authors.initials: B
authors.lastname: Kellam
authors.forename: David I
authors.initials: DI
authors.lastname: Pritchard
authors.forename: Peter M
authors.initials: PM
authors.lastname: Fischer
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000096:biosynthesis* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D006714:Homoserine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019169:Jurkat Cells; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D008163:Luminescent Measurements; D051379:Mice; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000502:physiology*; D053038:Quorum Sensing; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D001372:Aza Compounds; D001426:Bacterial Proteins; D007166:Immunosuppressive Agents; C080365:LasR protein, Pseudomonas aeruginosa; C109860:N-(3-oxododecanoyl)homoserine lactone; D015534:Trans-Activators; D006714:Homoserine; D015107:4-Butyrolactone