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Solid‐Phase Synthesis and Biological Evaluation of N ‐Dipeptido L ‐Homoserine Lactones as Quorum Sensing Activators
Author(s) -
Hansen Mette R.,
Le Quement Sebastian T.,
Jakobsen Tim H.,
Skovstrup Søren,
Taboureau Olivier,
TolkerNielsen Tim,
Givskov Michael,
Nielsen Thomas E.
Publication year - 2014
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201300533
Subject(s) - quorum sensing , biofilm , pseudomonas aeruginosa , bacteria , homoserine , in silico , chemistry , virulence , biochemistry , microbiology and biotechnology , biology , gene , genetics
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.