Solid‐Phase Synthesis and Biological Evaluation of N‐Dipeptido L‐Homoserine Lactones as Quorum Sensing Activators

Mette Reimert Hansen, Sebastian Thordal Le Quement, Tim Holm Jakobsen, Søren Skovstrup, Olivier Taboureau, Tim Tolker‐Nielsen, Michael Christian Givskov, Thomas Eiland Nielsen

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Abstract

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.
Original languageEnglish
JournalChemBioChem
Volume15
Issue number3
Pages (from-to)460-465
ISSN1439-4227
DOIs
Publication statusPublished - 2014

Cite this

Hansen, M. R., Le Quement, S. T., Jakobsen, T. H., Skovstrup, S., Taboureau, O., Tolker‐Nielsen, T., Givskov, M. C., & Nielsen, T. E. (2014). Solid‐Phase Synthesis and Biological Evaluation of N‐Dipeptido L‐Homoserine Lactones as Quorum Sensing Activators. ChemBioChem, 15(3), 460-465. https://doi.org/10.1002/cbic.201300533