Solid-phase synthesis and biological evaluation of N-dipeptido L-homoserine lactones as quorum sensing activators

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. Behind the screen: A virtual screening approach identified a number of N-dipeptido L-homo-serine lactones as potential quorum sensing modulators. Selected compounds were synthesized and identified as activators of LasR, a protein regulating quorum sensing in Pseudomonas aeruginosa; EC50 values were in the low micromolar range.

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. Behind the screen: A virtual screening approach identified a number of N-dipeptido L-homo-serine lactones as potential quorum sensing modulators. Selected compounds were synthesized and identified as activators of LasR, a protein regulating quorum sensing in Pseudomonas aeruginosa; EC50 values were in the low micromolar range.

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

SN - 1439-4227

VL - 15

SP - 460

EP - 465

JO - ChemBioChem

JF - ChemBioChem

IS - 3

ER -