β‐Cyclodextrin Encapsulation of Synthetic AHLs: Drug Delivery Implications and Quorum‐Quenching Exploits

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...

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Veröffentlicht in:Chembiochem : a European journal of chemical biology 2021-04, Vol.22 (7), p.1292-1301
Hauptverfasser: Ziegler, Eric W., Brown, Alan B., Nesnas, Nasri, Chouinard, Christopher D., Mehta, Anil K., Palmer, Andrew G.
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container_issue 7
container_start_page 1292
container_title Chembiochem : a European journal of chemical biology
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creator Ziegler, Eric W.
Brown, Alan B.
Nesnas, Nasri
Chouinard, Christopher D.
Mehta, Anil K.
Palmer, Andrew G.
description 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. A solution solution: Synthetic AHL analogues (SAHLAs) have demonstrated efficacy as quorum sensing inhibitors by receptor antagonism. However, like native AHLs, these compounds are poorly soluble. To improve their solubility, we investigated the association of three representative SAHLAs, and their hydrolysis products, with β‐cyclodextrin by spectrofluorimetry and evaluated co‐application of CDs with SAHLAs in a C. elegans infection model.Drug delivery implications and quorum‐quenching exploits of beta‐cyclodextrin encapsulation of synthetic AHLs (Palmer @FloridaTech)
doi_str_mv 10.1002/cbic.202000773
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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. A solution solution: Synthetic AHL analogues (SAHLAs) have demonstrated efficacy as quorum sensing inhibitors by receptor antagonism. However, like native AHLs, these compounds are poorly soluble. 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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. A solution solution: Synthetic AHL analogues (SAHLAs) have demonstrated efficacy as quorum sensing inhibitors by receptor antagonism. However, like native AHLs, these compounds are poorly soluble. 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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. A solution solution: Synthetic AHL analogues (SAHLAs) have demonstrated efficacy as quorum sensing inhibitors by receptor antagonism. However, like native AHLs, these compounds are poorly soluble. 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subjects Bacteria
Chemical synthesis
Cyclodextrins
Drug delivery
Encapsulation
Fluorescence
Fluorescence spectroscopy
fluorescence titration
Gram-negative bacteria
Homoserine lactones
host-guest chemistry
Hydrophobicity
Lactones
Magnetic resonance spectroscopy
Mass spectrometry
Mass spectroscopy
Microorganisms
NMR
Nuclear magnetic resonance
Pharmaceutical industry
Population density
Pseudomonas aeruginosa
Quorum sensing
Scientific imaging
synthetic AHL analogues
Virulence
β-Cyclodextrin
title β‐Cyclodextrin Encapsulation of Synthetic AHLs: Drug Delivery Implications and Quorum‐Quenching Exploits
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