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Certain bacteria use cell-to-cell chemical communication to coordinate community-wide phenotypic expression, including swarming motility, antibiotic biosynthesis, and biofilm production. Here we present a marine gram-positive bacterium that secretes secondary metabolites capable of quenching quorum sensing-controlled behaviors in several gram-negative reporter strains. Isolate C42, a Halobacillus salinus strain obtained from a sea grass sample, inhibits bioluminescence production by Vibrio harveyi in cocultivation experiments. With the use of bioassay-guided fractionation, two phenethylamide metabolites were identified as the active agents. The compounds additionally inhibit quorum sensing-regulated violacein biosynthesis by Chromobacterium violaceum CV026 and green fluorescent protein production by Escherichia coli JB525. Bacterial growth was unaffected at concentrations below 200 g/ml. Evidence is presented that these nontoxic metabolites may act as antagonists of bacterial quorum sensing by competing with N-acyl homoserine lactones for receptor binding.Taxonomically diverse marine bacteria have proven to be a rich resource for the discovery of structurally unique and bioactive secondary metabolites (5). Given the intense microbial competition for resources such as space and nutrients, it is probable that many excreted metabolites help mediate microbe-microbe interactions. Various antibiotics have been implicated as chemical defenses for marine bacteria, thus suggesting a role for the biosynthesis of toxic metabolites. For example, a pelagic Alteromonas species produces the antibiotic 2-n-pentyl-4-quinolinol, capable of influencing bacterial community structure on particles (25), and production of the antibiotic andrimid by a marine Vibrio species prevents colonization of surfaces by the particle specialist Vibrio cholerae (26).Though not yet widely studied, the secretion of nontoxic molecules could also play important roles in antagonistic marine microbial interactions. Quorum sensing pathways of competing bacteria are potential targets for such nontoxic chemical defenses. Bacterial communication is facilitated by the production and subsequent recognition of small signaling molecules (autoinducers) and can regulate important phenotypes, including bioluminescence, biofilm formation, swarming motility, antibiotic biosynthesis, and virulence factor production (3, 7, 15). Gram-negative bacteria commonly use N-acyl homoserine lactones (AHL) as signaling molecules, which bind their cognate receptor proteins to activate gene expression (10). These autoinducers share a conserved L-homoserine lactone moiety, and the length and sites of oxidation on the acyl chain dictate the species specificity (37). In contrast, gram-positive bacteria generally accomplish quorum sensing using posttranslationally modified peptides as autoinducers. For example, Staphylococcus aureus uses cyclic oligopeptides to regulate virulence factor production (11).Here we report the production of nontoxic secondary metabolites by a marine gram-pos...

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SUMMARY Honaucins A–C were isolated from the cyanobacterium Leptolyngbya crossbyana which was found overgrowing corals on the Hawaiian coast. Honaucin A consists of (S)-3-hydroxy-γ-butyrolactone and 4-chlorocrotonic acid which are connected via an ester linkage. Honaucin A and its two natural analogs exhibit potent inhibition of bioluminescence, a quorum sensing-dependent phenotype, in Vibrio harveyi BB120 as well as of lipopolysaccharide-stimulated nitric oxide production in the murine macrophage cell line RAW264.7. The decrease in nitric oxide production was accompanied by a decrease in the transcripts of several pro-inflammatory cytokines, most dramatically interleukin-1β. Synthesis of honaucin A as well as a number of analogs and subsequent evaluation in anti-inflammation and quorum sensing inhibition bioassays revealed the essential structural features for activity in this chemical class, and provided analogs with greater potency in both assays.