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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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Related in: MedlinePlus

Proposed model of action in enteric bacteria. Ester protected DPD analogs diffuse into the cell, where esterases hydrolyze the ester pro-DPD and analogs and the DPD or analogs are subsequently phosphorylated by LsrK.
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f6-sensors-12-03762: Proposed model of action in enteric bacteria. Ester protected DPD analogs diffuse into the cell, where esterases hydrolyze the ester pro-DPD and analogs and the DPD or analogs are subsequently phosphorylated by LsrK.

Mentions: In conclusion, we have shown that ester derivatives of DPD analogs can be hydrolyzed inside bacterial cells to reveal the biologically active diol unit for quorum sensing disruption. We reveal that it is possible to achieve selectivity of QS modulation amongst closely related bacteria (in our case, between E. coli and S. typhimurium) via the use of ester protection of the diol unit of AI-2. The origin of this selectivity remains unknown at this moment but it could be a number of several factors, including selective permeation of the analogs or different sensitivities of the esterases required for analog hydrolysis in the different bacteria (Figure 6). Future work will be aimed at obtaining a more in depth molecular understanding of these interesting observations. This work adds to the growing list of different strategies that can be used to intercept AI-2 signaling in diverse bacteria [13,35–38].


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)

Proposed model of action in enteric bacteria. Ester protected DPD analogs diffuse into the cell, where esterases hydrolyze the ester pro-DPD and analogs and the DPD or analogs are subsequently phosphorylated by LsrK.
© Copyright Policy
Related In: Results  -  Collection

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

f6-sensors-12-03762: Proposed model of action in enteric bacteria. Ester protected DPD analogs diffuse into the cell, where esterases hydrolyze the ester pro-DPD and analogs and the DPD or analogs are subsequently phosphorylated by LsrK.
Mentions: In conclusion, we have shown that ester derivatives of DPD analogs can be hydrolyzed inside bacterial cells to reveal the biologically active diol unit for quorum sensing disruption. We reveal that it is possible to achieve selectivity of QS modulation amongst closely related bacteria (in our case, between E. coli and S. typhimurium) via the use of ester protection of the diol unit of AI-2. The origin of this selectivity remains unknown at this moment but it could be a number of several factors, including selective permeation of the analogs or different sensitivities of the esterases required for analog hydrolysis in the different bacteria (Figure 6). Future work will be aimed at obtaining a more in depth molecular understanding of these interesting observations. This work adds to the growing list of different strategies that can be used to intercept AI-2 signaling in diverse bacteria [13,35–38].

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