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β‐Cyclodextrin Encapsulation of Synthetic AHLs: Drug Delivery Implications and Quorum‐Quenching Exploits
Author(s) -
Ziegler Eric W.,
Brown Alan B.,
Nesnas Nasri,
Chouinard Christopher D.,
Mehta Anil K.,
Palmer Andrew G.
Publication year - 2021
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.202000773
Subject(s) - quorum quenching , quorum sensing , chemistry , pseudomonas aeruginosa , virulence , homoserine , bacteria , small molecule , drug delivery , combinatorial chemistry , biochemistry , biology , organic chemistry , genetics , gene
Many bacteria, such as Pseudomonas aeruginosa , regulate phenotypic switching in a population density‐dependent manner through a phenomenon known as quorum sensing (QS). For Gram‐negative bacteria, QS relies on the synthesis, transmission, and perception of low‐molecular‐weight signal molecules that are predominantly N ‐acyl‐ l ‐homoserine lactones (AHLs). Efforts to disrupt AHL‐mediated QS have largely focused on the development of synthetic AHL analogues (SAHLAs) that are structurally similar to native AHLs. However, like AHLs, these molecules tend to be hydrophobic and are poorly soluble under aqueous conditions. Water‐soluble macrocycles, such as cyclodextrins (CDs), that encapsulate hydrophobic guests have long been used by both the agricultural and pharmaceutical industries to overcome the solubility issues associated with hydrophobic compounds of interest. Conveniently, CDs have also demonstrated anti‐AHL‐mediated QS effects. Here, using fluorescence spectroscopy, NMR spectrometry, and mass spectrometry, we evaluate the affinity of SAHLAs, as well as their hydrolysis products, for β‐CD inclusion. We also evaluated the ability of these complexes to inhibit wild‐type P. aeruginosa virulence in a Caenorhabditis elegans host infection study, for the first time. Our efforts confirm the potential of β‐CDs for the improved delivery of SAHLAs at the host/microbial interface, expanding the utility of this approach as a strategy for probing and controlling QS.