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.
Frezza
Marine
M
Laboratoire de Chimie Organique, UMR CNRS-UCBL-INSA 5181, Institut National des Sciences Appliquées, 20 avenue A. Einstein, 69621 Villeurbanne, France.
Castang
Sandra
S
Estephane
Jane
J
Soulère
Laurent
L
Deshayes
Christian
C
Chantegrel
Bernard
B
Nasser
William
W
Queneau
Yves
Y
Reverchon
Sylvie
S
Doutheau
Alain
A
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