Solid-phase synthesis and biological evaluation of N-dipeptido L-homoserine lactones as quorum sensing activators
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Solid-phase synthesis and biological evaluation of N-dipeptido L-homoserine lactones as quorum sensing activators. / Hansen, Mette R; Le Quement, Sebastian T; Jakobsen, Tim H; Skovstrup, Søren; Taboureau, Olivier; Tolker-Nielsen, Tim; Givskov, Michael; Nielsen, Thomas E.
In: ChemBioChem, Vol. 15, No. 3, 10.02.2014, p. 460-5.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Solid-phase synthesis and biological evaluation of N-dipeptido L-homoserine lactones as quorum sensing activators
AU - Hansen, Mette R
AU - Le Quement, Sebastian T
AU - Jakobsen, Tim H
AU - Skovstrup, Søren
AU - Taboureau, Olivier
AU - Tolker-Nielsen, Tim
AU - Givskov, Michael
AU - Nielsen, Thomas E
N1 - Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2014/2/10
Y1 - 2014/2/10
N2 - Bacteria use small signaling molecules to communicate in a process termed "quorum sensing" (QS), which enables the coordination of survival strategies, such as production of virulence factors and biofilm formation. In Gram-negative bacteria, these signaling molecules are a series of N-acylated L-homoserine lactones. With the goal of identifying non-native compounds capable of modulating bacterial QS, a virtual library of N-dipeptido L-homoserine lactones was screened in silico with two different crystal structures of LasR. The 30 most promising hits were synthesized on HMBA-functionalized PEGA resin and released through an efficient acid-mediated cyclative release mechanism. Subsequent screening for modulation of QS in Pseudomonas aeruginosa and E. coli identified six moderately strong activators. A follow-up library designed from the preliminary derived structure-activity relationships was synthesized and evaluated for their ability to activate the QS system in this bacterium. This resulted in the identification of another six QS activators (two with low micromolar activity) thus illuminating structural features required for QS modulation.
AB - Bacteria use small signaling molecules to communicate in a process termed "quorum sensing" (QS), which enables the coordination of survival strategies, such as production of virulence factors and biofilm formation. In Gram-negative bacteria, these signaling molecules are a series of N-acylated L-homoserine lactones. With the goal of identifying non-native compounds capable of modulating bacterial QS, a virtual library of N-dipeptido L-homoserine lactones was screened in silico with two different crystal structures of LasR. The 30 most promising hits were synthesized on HMBA-functionalized PEGA resin and released through an efficient acid-mediated cyclative release mechanism. Subsequent screening for modulation of QS in Pseudomonas aeruginosa and E. coli identified six moderately strong activators. A follow-up library designed from the preliminary derived structure-activity relationships was synthesized and evaluated for their ability to activate the QS system in this bacterium. This resulted in the identification of another six QS activators (two with low micromolar activity) thus illuminating structural features required for QS modulation.
KW - Acyl-Butyrolactones
KW - Bacterial Proteins
KW - Binding Sites
KW - Dipeptides
KW - Molecular Docking Simulation
KW - Protein Binding
KW - Protein Structure, Tertiary
KW - Pseudomonas aeruginosa
KW - Quorum Sensing
KW - Solid-Phase Synthesis Techniques
KW - Trans-Activators
U2 - 10.1002/cbic.201300533
DO - 10.1002/cbic.201300533
M3 - Journal article
C2 - 24436223
VL - 15
SP - 460
EP - 465
JO - ChemBioChem
JF - ChemBioChem
SN - 1439-4227
IS - 3
ER -
ID: 129018641