Bacteria secrete and respond to small chemical signals, or autoinducers, in a cell densitydependent 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. 2,3One 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 of agonists or antagonists for this system would have implications for broad range QS modulation.Despite the wide distribution of the AI-2 synthase LuxS, the discrete structures of DPD-based autoinducers and their respective receptor proteins have only been identified in two species: V. harveyi and S. typhimurium. These two signals are distinct despite the fact that both are derived from DPD and rapidly interconvert in solution: S. typhimurium responds to the Rtetrahydroxytetrahydrofuran (R-THMF) form of DPD, whereas V. harveyi responds to the S-THMF borate diester form of DPD (Supporting Information, Figure S1). 4 This lack of structural information has been detrimental to the development of agonists and antagonists of AI-2-based QS, and reports of modulators of this system remain limited. Several reports have identified weak and partial agonists, 7-9 while reports of antagonists remain largely limited to one class of natural products. 10,11 Because of this dearth of information regarding the modulation of AI-2 QS, there is no solid rationale for the design of new ligands. Herein, we report the discovery of a class of synergistic compounds toward the QS of V. harveyi, as well as a remarkable switch in the biological transmission of AI-2-based QS in S. typhimurium stemming from the addition of methylene groups to the C1 position of DPD. E-mail: kdjanda@scripps.edu. Supporting Information Available: Experimental procedures, spectral data, and biological protocols. This material is available free of charge via the Internet at http://pubs.acs.org. As a first step toward the discovery of new modulators of AI-2-based QS, we created a panel of C1-substituted DPD analogues according to Scheme 1. The synthesis is founded upon previous...
In Nature, bacteria rarely exist as single, isolated entities, but rather as communities comprised of many other species including higher host organisms. To survive in these competitive environments, microorganisms have developed elaborate tactics such as the formation of biofilms and the production of antimicrobial toxins. Recently, it was discovered that the Gram-negative bacterium Pseudomonas aeruginosa, an opportunistic human pathogen, produces an antibiotic, 3-(1-hydroxydecylidene)-5-(2-hydroxyethyl)pyrrolidine-2,4-dione (C 12 -TA), derived from one of its quorum sensing molecules. Here, we present a comprehensive study of the expanded spectrum of C 12 -TA antibacterial activity against microbial competitors encountered by P. aeruginosa in Nature as well as significant human pathogens. The mechanism of action of C 12 -TA was also elucidated and C 12 -TA was found to dissipate both the membrane potential and pH gradient of Gram-positive bacteria, correlating well with cell death. Notably, in stark contrast to its parent molecule 3-oxododecanoyl homoserine lactone (3-oxo-C 12 -HSL), neither activation of cellular stress pathways nor cytotoxicity was observed in human cells treated with C 12 -TA. Our results suggest that the QS machinery of P. aeruginosa has evolved for a dual-function, both to signal others of the same species, and also to defend against both host immunity and competing bacteria. Because of the broad-spectrum antibacterial activity, established mode of action, lack of rapid resistance development, and tolerance by human cells, the C 12 -TA scaffold may also serve as a new lead compound for the development of antimicrobial therapeutics.
Quorum sensing (QS) has traditionally referred to a mechanism of communication within a species of bacteria. However, emerging research implicates QS in interspecies communication and competition, and such systems have been proposed in a wide variety of bacteria. This activity of bacterial QS also extends to relationships between bacteria and eukaryotes and host-pathogen interactions in both clinical and agricultural settings are of particular interest. These relationships are particularly pertinent in light of the rising prevalence of antibiotic resistant bacteria. In this tutorial review we describe bacterial QS and its capacity in interspecies and interkingdom interactions, as well as the corresponding eukaryotic responses.
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