Synthetic analogs tailor native AI-2 signaling across bacterial species.

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TitleSynthetic analogs tailor native AI-2 signaling across bacterial species.
Publication TypeJournal Article
Year of Publication2010
AuthorsRoy, V, Smith, JAI, Wang, J, Stewart, JE, Bentley, WE, Sintim, HO
JournalJ Am Chem Soc
Date Published2010 Aug 18
KeywordsBacteria, Biological Transport, Ecosystem, Homoserine, Lactones, Models, Molecular, Molecular Conformation, Pentanes, Phosphorylation, Quorum Sensing

The widespread use of antibiotics and the emergence of resistant strains call for new approaches to treat bacterial infection. Bacterial cell-cell communication or "quorum sensing" (QS) is mediated by "signatures" of small molecules that represent targets for "quenching" communication and avoiding virulent phenotypes. Only a handful of small molecules that antagonize the action of the "universal" autoinducer, AI-2, have been reported. The biological basis of antagonism, as well as the targets for these select few AI-2 antagonists, have not been clearly defined. We have developed C-1 alkyl analogs of AI-2 that quench the QS response in multiple bacterial species simultaneously. We also demonstrate the biological basis for this action. Like AI-2, the analogs are activated by the bacterial kinase, LsrK, and modulate AI-2 specific gene transcription through the transcriptional regulator, LsrR. Interestingly, addition of a single carbon to the C1-alkyl chain of the analog plays a crucial role in determining the effect of the analog on the QS response. While an ethyl modified analog is an agonist, propyl becomes an antagonist of the QS circuit. In a trispecies synthetic ecosystem comprised of E. coli, S. typhimurium, and V. harveyi we discovered both cross-species and species-specific anti-AI-2 QS activities. Our results suggest entirely new modalities for interrupting or tailoring the network of communication among bacteria.

Alternate JournalJ. Am. Chem. Soc.
PubMed ID20698680