title: Probing autoinducer-2 based quorum sensing: the biological consequences of molecules unable to traverse equilibrium states.
abstract: Bacteria have developed a cell-to-cell communication system, termed quorum sensing (QS), which allows for the population-dependent coordination of their behavior via the exchange of chemical signals. Autoinducer-2 (AI-2), a class of QS signals derived from 4,5-dihydroxy-2,3-pentandione (DPD), has been revealed as a universal signaling molecule in a variety of bacterial species. In spite of considerable interest, the study of putative AI-2 based QS systems remains a challenging topic in part due to the rapid interconversion between the linear and cyclic forms of DPD. Herein, we report the design and development of efficient syntheses of carbocyclic analogues of DPD, which are locked in the cyclic form. The synthetic analogues were evaluated for the modulation of AI-2-based QS in Vibrio harveyi and Salmonella typhimurium. No agonists were uncovered in either V. harveyi or S. typhimurium assay, whereas weak to moderate antagonists were found against V. harveyi. On the basis of NMR analyses and DFT calculations, the heterocyclic oxygen atom within DPD appears necessary to promote hydration at the C3 position of cyclic DPD to afford the active tetrahydroxy species. These results also shed light on the interaction between the heterocyclic oxygen atom and receptor proteins as well as the importance of the linear form and dynamic equilibrium of DPD as crucial requirements for activation of AI-2 based QS circuits.
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Kyoji
authors.initials: K
authors.lastname: Tsuchikama
authors.forename: Colin A
authors.initials: CA
authors.lastname: Lowery
authors.forename: Kim D
authors.initials: KD
authors.lastname: Janda
mesh_terms: D006714:Homoserine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010422:Pentanones / Q000138:chemical synthesis / Q000737:chemistry; D011789:Quantum Theory; D053038:Quorum Sensing; D012486:Salmonella typhimurium / Q000737:chemistry / Q000378:metabolism; D014733:Vibrio / Q000737:chemistry / Q000378:metabolism
chemical_list: D007783:Lactones; C091088:N-octanoylhomoserine lactone; D010422:Pentanones; C008790:acetylacetone; D006714:Homoserine