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A pro-drug approach for selective modulation of AI-2-mediated bacterial cell-to-cell communication.

Guo M, Gamby S, Nakayama S, Smith J, Sintim HO - Sensors (Basel) (2012)

Bottom Line: Analogs of AI-2 have the potential to modulate bacterial behavior.Herein, we demonstrate that when an AI-2 analog, isobutyl DPD (which has been previously shown to be a quorum sensing, QS, quencher in both Escherichia coli and Salmonella typhimurium) is modified with ester groups, which get hydrolyzed once inside the bacterial cells, only QS in E. coli, but not in S. typhimurium, is inhibited.The origin of this differential QS inhibition could be due to differences in analog permeation of the bacterial membranes or ester hydrolysis rates.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA. mguo@umd.edu

ABSTRACT
The universal quorum sensing autoinducer, AI-2, is utilized by several bacteria. Analogs of AI-2 have the potential to modulate bacterial behavior. Selectively quenching the communication of a few bacteria, in the presence of several others in an ecosystem, using analogs of AI-2 is non-trivial due to the ubiquity of AI-2 processing receptors in many bacteria that co-exist. Herein, we demonstrate that when an AI-2 analog, isobutyl DPD (which has been previously shown to be a quorum sensing, QS, quencher in both Escherichia coli and Salmonella typhimurium) is modified with ester groups, which get hydrolyzed once inside the bacterial cells, only QS in E. coli, but not in S. typhimurium, is inhibited. The origin of this differential QS inhibition could be due to differences in analog permeation of the bacterial membranes or ester hydrolysis rates. Such differences could be utilized to selectively target QS in specific bacteria amongst a consortium of other species that also use AI-2 signaling.

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Synthetic strategy for making bis-ester protected AI-2 analogs.Reagents and conditions: (a) diazomethane, 0 °C; (b) tert-butyl-siloxyacetaldehyde, DBU (1,8 diazabicycloundec-7-ene), CH3CN, RT; (c) TBAF/THF. DCM = dichloromethane; DMDO = dimethyldioxirane.
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f7-sensors-12-03762: Synthetic strategy for making bis-ester protected AI-2 analogs.Reagents and conditions: (a) diazomethane, 0 °C; (b) tert-butyl-siloxyacetaldehyde, DBU (1,8 diazabicycloundec-7-ene), CH3CN, RT; (c) TBAF/THF. DCM = dichloromethane; DMDO = dimethyldioxirane.

Mentions: The syntheses of bis-ester protected AI-2 and analogs 19–30 were achieved via the strategy shown in Scheme 1 [20,28]. Briefly, an aldol reaction between diazocarbonyls 1–3 and 2-(tert-butyldimethylsilyloxy) acetaldehyde afforded diazodiols 4–6, after deprotection of the TBS group with TBAF. Oxidation of the diazo group in diazodiols 4–6 afforded AI-2 or analogs but for the production of ester protected AI-2 and analogs, it was important to perform the esterification step first to give bis-ester 7–18 before the oxidation of the diazo bis-ester to give targeted compounds 19–30.


A pro-drug approach for selective modulation of AI-2-mediated bacterial cell-to-cell communication.

Guo M, Gamby S, Nakayama S, Smith J, Sintim HO - Sensors (Basel) (2012)

Synthetic strategy for making bis-ester protected AI-2 analogs.Reagents and conditions: (a) diazomethane, 0 °C; (b) tert-butyl-siloxyacetaldehyde, DBU (1,8 diazabicycloundec-7-ene), CH3CN, RT; (c) TBAF/THF. DCM = dichloromethane; DMDO = dimethyldioxirane.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3376627&req=5

f7-sensors-12-03762: Synthetic strategy for making bis-ester protected AI-2 analogs.Reagents and conditions: (a) diazomethane, 0 °C; (b) tert-butyl-siloxyacetaldehyde, DBU (1,8 diazabicycloundec-7-ene), CH3CN, RT; (c) TBAF/THF. DCM = dichloromethane; DMDO = dimethyldioxirane.
Mentions: The syntheses of bis-ester protected AI-2 and analogs 19–30 were achieved via the strategy shown in Scheme 1 [20,28]. Briefly, an aldol reaction between diazocarbonyls 1–3 and 2-(tert-butyldimethylsilyloxy) acetaldehyde afforded diazodiols 4–6, after deprotection of the TBS group with TBAF. Oxidation of the diazo group in diazodiols 4–6 afforded AI-2 or analogs but for the production of ester protected AI-2 and analogs, it was important to perform the esterification step first to give bis-ester 7–18 before the oxidation of the diazo bis-ester to give targeted compounds 19–30.

Bottom Line: Analogs of AI-2 have the potential to modulate bacterial behavior.Herein, we demonstrate that when an AI-2 analog, isobutyl DPD (which has been previously shown to be a quorum sensing, QS, quencher in both Escherichia coli and Salmonella typhimurium) is modified with ester groups, which get hydrolyzed once inside the bacterial cells, only QS in E. coli, but not in S. typhimurium, is inhibited.The origin of this differential QS inhibition could be due to differences in analog permeation of the bacterial membranes or ester hydrolysis rates.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA. mguo@umd.edu

ABSTRACT
The universal quorum sensing autoinducer, AI-2, is utilized by several bacteria. Analogs of AI-2 have the potential to modulate bacterial behavior. Selectively quenching the communication of a few bacteria, in the presence of several others in an ecosystem, using analogs of AI-2 is non-trivial due to the ubiquity of AI-2 processing receptors in many bacteria that co-exist. Herein, we demonstrate that when an AI-2 analog, isobutyl DPD (which has been previously shown to be a quorum sensing, QS, quencher in both Escherichia coli and Salmonella typhimurium) is modified with ester groups, which get hydrolyzed once inside the bacterial cells, only QS in E. coli, but not in S. typhimurium, is inhibited. The origin of this differential QS inhibition could be due to differences in analog permeation of the bacterial membranes or ester hydrolysis rates. Such differences could be utilized to selectively target QS in specific bacteria amongst a consortium of other species that also use AI-2 signaling.

Show MeSH
Related in: MedlinePlus