Synthetic analogs tailor native AI-2 signaling across bacterial species

J Am Chem Soc. 2010 Aug 18;132(32):11141-50. doi: 10.1021/ja102587w.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Bacteria / cytology*
  • Bacteria / drug effects*
  • Bacteria / metabolism
  • Biological Transport
  • Ecosystem
  • Homoserine / analogs & derivatives*
  • Homoserine / antagonists & inhibitors
  • Homoserine / chemistry
  • Homoserine / metabolism
  • Lactones / antagonists & inhibitors
  • Lactones / chemistry*
  • Lactones / metabolism*
  • Models, Molecular
  • Molecular Conformation
  • Pentanes / chemical synthesis*
  • Pentanes / chemistry
  • Pentanes / metabolism
  • Pentanes / pharmacology*
  • Phosphorylation
  • Quorum Sensing / drug effects*


  • 4,5-dihydroxy-2,3-pentanedione
  • Lactones
  • N-octanoylhomoserine lactone
  • Pentanes
  • Homoserine