A Pro-Drug Approach for Selective Modulation of AI-2-Mediated Bacterial Cell-to-Cell Communication

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.

Development of Quorum-Based Anti-Virulence Therapeutics Targeting Gram-Negative Bacterial Pathogens

“…On the other hand, analogues of DPD can also be used for quorum sensing inhibition in the bacterium. Guo et al demonstrated that ester derivatives of DPD analogues introduced into E. coli can be hydrolyzed subsequently inside the cells to reveal a biologically active diol functional group for quorum sensing disruption [128]. Interestingly, when identical DPD analogues were delivered into S. typhimurium , a similar disruption effect was not observed, suggesting that selective quorum sensing modulation could possibly be achieved between closely related species using this type of ester-linked compound.…”

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

“…One concern for in vivo efficacy is the general instability of AI-2 molecules. However, Guo and colleagues recently demonstrated that a bis-ester-protected "prodrug" form of isobutyl-DPD effectively inhibited AI-2-based quorum sensing in E. coli comparably to the unprotected inhibitor (216). Furthermore, the bis-ester-protected isobutyl-DPD was a selective antagonist for E. coli despite the fact that the unprotected analogue antagonized AI-2-mediated quorum sensing in both E. coli and S. Typhimurium (216).…”

“…However, Guo and colleagues recently demonstrated that a bis-ester-protected "prodrug" form of isobutyl-DPD effectively inhibited AI-2-based quorum sensing in E. coli comparably to the unprotected inhibitor (216). Furthermore, the bis-ester-protected isobutyl-DPD was a selective antagonist for E. coli despite the fact that the unprotected analogue antagonized AI-2-mediated quorum sensing in both E. coli and S. Typhimurium (216). The reason for this selectivity was not elucidated, but it was reasoned to be the result of differential diffusion of the prodrug into the cells and/or activation of the prodrug following permeation.…”

“…The reason for this selectivity was not elucidated, but it was reasoned to be the result of differential diffusion of the prodrug into the cells and/or activation of the prodrug following permeation. In either event, ester analogues of AI-2 derivatives may prove helpful in alleviating instability issues of these types of molecules while simultaneously increasing target selectivity (216).…”

Strategies for Silencing Bacterial Communication

“…Guo et al recently demonstrated that a bis-ester-protected form of isobutyl-DPD can effectively inhibit the AI-2 QS signalling in E. coli comparably to the unprotected inhibitor alleviating instability issues of AI-2 molecules (Lowery et al 2009;Guo et al 2012). …”