title: Synthetic analogs tailor native AI-2 signaling across bacterial species.
abstract: 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.
authors.affiliation: Graduate Program in Molecular and Cell Biology, University of Maryland, College Park, Maryland 20742, USA.
authors.forename: Varnika
authors.initials: V
authors.lastname: Roy
authors.forename: Jacqueline A I
authors.initials: JA
authors.lastname: Smith
authors.forename: Jingxin
authors.initials: J
authors.lastname: Wang
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Stewart
authors.forename: William E
authors.initials: WE
authors.lastname: Bentley
authors.forename: Herman O
authors.initials: HO
authors.lastname: Sintim
mesh_terms: D001419:Bacteria / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D001692:Biological Transport; D017753:Ecosystem; D006714:Homoserine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D007783:Lactones / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D010420:Pentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation; D053038:Quorum Sensing / Q000187:drug effects*
chemical_list: C493138:4,5-dihydroxy-2,3-pentanedione; D007783:Lactones; C091088:N-octanoylhomoserine lactone; D010420:Pentanes; D006714:Homoserine