Synthesis and biological evaluation of homoserine lactone derived ureas as antagonists of bacterial quorum sensing.
A series of 15 racemic alkyl- and aryl-N-substituted ureas, derived from homoserine lactone, were synthesized and tested for their ability to competitively inhibit the action of 3-oxohexanoyl-l-homoserine lactone, the natural inducer of bioluminescence in the bacterium Vibrio fischeri. N-alkyl ureas with an alkyl chain of at least 4 carbon atoms, as well as certain ureas bearing a phenyl group at the extremity of the alkyl chain, were found to be significant antagonists. In the case of N-butyl urea, it has been shown that the antagonist activity was related to the inhibition of the dimerisation of the N-terminal domain of ExpR, a protein of the receptor LuxR family. Molecular modelling suggested that this would result from the formation of an additional hydrogen bond in the protein acylhomoserine lactone binding cavity.
Laboratoire de Chimie Organique, UMR CNRS-UCBL-INSA 5181, Institut National des Sciences Appliquées, 20 avenue A. Einstein, 69621 Villeurbanne, France.
Marine
M
Frezza
Sandra
S
Castang
Jane
J
Estephane
Laurent
L
Soulère
Christian
C
Deshayes
Bernard
B
Chantegrel
William
W
Nasser
Yves
Y
Queneau
Sylvie
S
Reverchon
Alain
A
Doutheau
D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D048908:Aliivibrio fischeri / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D001665:Binding Sites; D004269:DNA, Bacterial / Q000235:genetics; D019281:Dimerization; D049449:Luminescence; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D004269:DNA, Bacterial; D012097:Repressor Proteins; D015534:Trans-Activators; C064778:LuxR autoinducer binding proteins; C088386:homoserine lactone; D014508:Urea; D015107:4-Butyrolactone