Synthesis of N-acyl homoserine lactone analogues reveals strong activators of SdiA, the Salmonella enterica serovar Typhimurium LuxR homologue.
N-Acyl homoserine lactones (AHLs) are molecules that are synthesized and detected by many gram-negative bacteria to monitor the population density, a phenomenon known as quorum sensing. Salmonella enterica serovar Typhimurium is an exceptional species since it does not synthesize its own AHLs, while it does encode a LuxR homologue, SdiA, which enables this bacterium to detect AHLs that are produced by other species. To obtain more information about the specificity of the ligand binding by SdiA, we synthesized and screened a limited library of AHL analogues. We identified two classes of analogues that are strong activators of SdiA: the N-(3-oxo-acyl)-homocysteine thiolactones (3O-AHTLs) and the N-(3-oxo-acyl)-trans-2-aminocyclohexanols. To our knowledge, this is the first report of compounds (the 3O-AHTLs) that are able to activate a LuxR homologue at concentrations that are lower than the concentrations of the most active AHLs. SdiA responds with greatest sensitivity to AHTLs that have a keto modification at the third carbon atom and an acyl chain that is seven or eight carbon atoms long. The N-(3-oxo-acyl)-trans-2-aminocyclohexanols were found to be less sensitive to deactivation by lactonase and alkaline pH than the 3O-AHTLs and the AHLs are. We also examined the activity of our library with LuxR of Vibrio fischeri and identified three new inhibitors of LuxR. Finally, we performed preliminary binding experiments which suggested that SdiA binds its activators reversibly. These results increase our understanding of the specificity of the SdiA-ligand interaction, which could have uses in the development of anti-quorum-sensing-based antimicrobials.
Janssens
Joost C A
JC
Centre of Microbial and Plant Genetics, Katholieke Universiteit Leuven, Kasteelpark Arenberg 20, B-3001 Leuven, Belgium.
Metzger
Kristine
K
Daniels
Ruth
R
Ptacek
Dave
D
Verhoeven
Tine
T
Habel
Lothar W
LW
Vanderleyden
Jos
J
De Vos
Dirk E
DE
De Keersmaecker
Sigrid C J
SC
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D001426:Bacterial Proteins / Q000187:drug effects* / Q000378:metabolism*; D003511:Cyclohexanols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015964:Gene Expression Regulation, Bacterial; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D053038:Quorum Sensing; D012097:Repressor Proteins / Q000737:chemistry; D012486:Salmonella typhimurium / Q000254:growth & development* / Q000378:metabolism; D015534:Trans-Activators / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*
D001426:Bacterial Proteins; D003511:Cyclohexanols; D012097:Repressor Proteins; C097686:SdiA protein, bacteria; D015534:Trans-Activators; D006710:Homocysteine; C064778:LuxR autoinducer binding proteins; C088386:homoserine lactone; C007957:homocysteine thiolactone; D015107:4-Butyrolactone