Posted by In this work, acyl homoserine lactones (AHLs) were grafted, the most studied signaling molecules in many Gram-negative bacteria, onto cyclodextrins (CDs) by copper-catalyzed azide–alkyne cycloaddition “click” coupling between alkynyl-AHLs and 6-azido-CDs derived from α- and βCD, native or methylated. Attaching biomolecules onto a CD scaffold is a known strategy to enhance their properties, but designing CD-AHL conjugates has never been reported. These molecules were fully characterized by NMR and high-resolution mass spectrometry, and the study of their solubility and conformation reveals significant conformational changes due to the presence of the AHL appendage on the CD structure. One of the hybrids (per-AHL-β-CD, 9B) exhibited higher solubility in water than AHL and β-CD alone. The new CD-AHLs conjugates were found to modulate bioluminescence in a quorum sensing LuxR-regulated light-producing bacterial model, with significant variations depending on the structure. The perAHL-β-CD, 9B, was found to be the most active compound in the series.
Several CD-AHLs conjugates were successfully synthesized and purified. The study of modulation of LuxR-regulated bioluminescence production showed that per-AHL-β-CD 9B was not only able to induce bioluminescence with an EC50 value of 64 μM but also to reduce bioluminescence with an IC50 value of 10–20 μM. This initial investigation suggests that AHL-β-CD conjugates have improved efficacy compared to αCD analogs. The presence of free secondary hydroxyl groups and the persubstitution of CD by the AHL moieties appear to be crucial. In order to better understand the phenomena and the mechanism involved, the synthesis of new derivatives is underway to assess the relevance of linker length and triazole function in modulating LuxR-regulated bioluminescence production.
Nicolas Tinet, David Lesur, Yves Queneau, Laurent Soulère, Florence Djedaini-Pilard, Véronique Bonnet (2025) Effects on LuxR‐Regulated Bioluminescence of Cyclodextrin‐Acyl‐L‐Homoserine Lactone Hybrids. ChemBioChem 26, e202500525. https://doi.org/10.1002/cbic.202500525