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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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Compounds evaluated as bis-ester protected AI-2 analogs.
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f2-sensors-12-03762: Compounds evaluated as bis-ester protected AI-2 analogs.

Mentions: With the various AI-2 or analog ester derivatives (methyl to pentyl esters, Figure 2) in hand, we proceeded to investigate the biological profiles of these esters. We have previously demonstrated that AI-2 analogs with longer C1-acyl chains permeate more readily into bacterial cells than shorter chains [31]. This is presumably due to the favorable interactions of the alkyl chain with the phospholipid of the bacterial membrane. Based on this earlier work, we hypothesized that the longer chain ester derivatives (such as butyl or pentyl) would permeate more readily into bacterial cells than the shorter chain analogs, such as the methyl ester series [31]. However, if the cellular esterases were sensitive to the size of the esters, then the longer chain analogs would be hydrolyzed slower than the shorter chain ones. Because biological activity of ester prodrugs is dependent on permeation and prodrug activation and both of these processes would depend on the organism in question, it is not always easy to predict a priori which ester group is most suitable for derivatizing biologically active molecules.


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)

Compounds evaluated as bis-ester protected AI-2 analogs.
© Copyright Policy
Related In: Results  -  Collection

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

f2-sensors-12-03762: Compounds evaluated as bis-ester protected AI-2 analogs.
Mentions: With the various AI-2 or analog ester derivatives (methyl to pentyl esters, Figure 2) in hand, we proceeded to investigate the biological profiles of these esters. We have previously demonstrated that AI-2 analogs with longer C1-acyl chains permeate more readily into bacterial cells than shorter chains [31]. This is presumably due to the favorable interactions of the alkyl chain with the phospholipid of the bacterial membrane. Based on this earlier work, we hypothesized that the longer chain ester derivatives (such as butyl or pentyl) would permeate more readily into bacterial cells than the shorter chain analogs, such as the methyl ester series [31]. However, if the cellular esterases were sensitive to the size of the esters, then the longer chain analogs would be hydrolyzed slower than the shorter chain ones. Because biological activity of ester prodrugs is dependent on permeation and prodrug activation and both of these processes would depend on the organism in question, it is not always easy to predict a priori which ester group is most suitable for derivatizing biologically active molecules.

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