An unexpected switch in the modulation of AI-2-based quorum sensing discovered through synthetic 4,5-dihydroxy-2,3-pentanedione analogues

Bacteria secrete and respond to small chemical signals, or autoinducers, in a cell density-dependent process known as quorum sensing (QS).1 As the number of cells, and consequently autoinducer concentration, increases, bacterial populations coordinate their gene expression to behave as a unified group. This coordinated effort of bacteria might result in deleterious effects for humans, as certain bacteria use QS to regulate the formation of biofilms and the secretion of virulence factors. As a result, the modulation of QS has emerged as a therapeutic target of considerable interest.2,3 One class of autoinducers is AI-2, derived from the precursor (S)-4,5-dihydroxy-2,3-pentanedione (DPD), and the gene encoding the DPD synthase, LuxS, has been identified in over 55 bacterial species.4 QS systems based on this autoinducer have been shown to regulate bioluminescence in Vibrio harveyi, virulence and biofilm formation in Vibrio cholera, AI-2 transport and virulence expression in Salmonella typhimurium, and mixed-species biofilm development in oral pathogens.5,6 Illustrated in this final example is the fact that AI-2 QS, in contrast to other QS systems that are used for communication between members of the same species, serves as a mechanism of interspecies communication.4 Thus, the development o