Comparative Analyses of <i>N</i>‐Acylated Homoserine Lactones Reveal Unique Structural Features that Dictate Their Ability to Activate or Inhibit Quorum Sensing

Geske, Grant D.; O’Neill, Jennifer C.; Miller, David M.; Wezeman, Rachel J.; Mattmann, Margrith E.; Lin, Qi; Blackwell, Helen E.

doi:10.1002/cbic.200700551

Cited by 100 publications

(212 citation statements)

References 35 publications

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“…The type of oxygenated functional group also appears to impact the strength these QS mimics, with the furans tested (Compounds 9 and 10) having higher activities than the È lactones (Compounds 2-5). In keeping with our current understanding of the QS mechanism, QS interference was only observed for cembranoid diterpenes possessing secondary oxygen rings (Fuqua et al, 2001;Watson et al, 2002;Geske et al, 2008). The presence of other minor functional groups (epoxides, acetates or level of saturation) had minimal discernible impact on the strength of QS interference observed and no obvious effect on the type of activity observed with respect to A. tumefaciens A136.…”

Section: Pure Compoundssupporting

confidence: 51%

“…Multiple QS systems have been discovered; in Gram-negative bacteria (Papenfort and Bassler, 2016) the most well studied system is the Auto Inducer One system (AI-1), which utilizes acyl homoserine lactones (AHLs) as signal molecules. Studies into the structure and functions of AHLs suggest that the G-lactone ring is required for QS activity and that the length and functionality of the acyl side chain provides specificity (Parsek and Greenberg, 2000;Watson et al, 2002;Geske et al, 2008). For this reason, it has been hypothesized that AI-1 QS mimics would also contain a G lactone ring or homologous functionality such as the furanones of the red alga Delisea pulchra.…”

Section: Introductionmentioning

confidence: 99%

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Quorum Sensing Interference and Structural Variation of Quorum Sensing Mimics in Australian Soft Coral

2018

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Bacterial Quorum Sensing (QS), the indirect regulation of gene expression through production and detection of small diffusible molecules, has emerged as a point of interaction between eukaryotic host organisms and their associated microbial communities. The extracellular nature of QS molecules enables interference in QS systems, in many cases via mimicry. This study targeted QS induction and inhibition in soft coral holobionts, as many soft coral species commonly contain compounds with structural similarities to the well-studied bacterial QS molecules acyl homoserine lactones. Screening with two bacterial biosensors, Agrobacterium tumefaciens A136 and Chromobacterium violaceum CV026, demonstrated that QS interference differed between the two biosensor strains and extended across the soft coral families Alcyoniidae, Clavulariidae, Nephtheidae, and Xeniidae. Bioassay-guided fractionation revealed chemical activity patterns, particularly in the induction of QS. Cembranoid diterpenes from active fractions were purified and tested for QS interference activity. Interestingly, the type of QS activity (induction or inhibition) in A. tumefaciens A136 correlated with structural variability of the secondary oxygen ring; cembranoid diterpenes with a furan ring or five-membered lactone induced QS, while compounds with larger (six or seven membered) lactone rings inhibited QS. Addition of the dominant cembranoid diterpene in the soft coral Lobophytum compactum, isolobophytolide, to bacterial culture media increased the number and morphological diversity of bacteria recovered from the mucosal layer of this soft coral, demonstrating a selective effect on certain members of the soft coral bacterial community. The identity and QS activity of recovered isolates differed between the mucosal layers of L. compactum and Sinularia flexibilis. In conclusion, this study provides information on the complexity of the interaction between soft corals and their associated bacteria, as well as, a structural understanding of how QS mimic compounds are able to interfere with a bacterial communication system.

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Section: Pure Compoundssupporting

confidence: 51%

Section: Introductionmentioning

confidence: 99%

Quorum Sensing Interference and Structural Variation of Quorum Sensing Mimics in Australian Soft Coral

2018

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“…In synthetic studies that have targeted the creation of quorum sensing antagonists based on AHL structural motifs, inhibitors have been designed with a phenyl ring appended to either the end of the acyl chain or replacing the lactone ring. For example, 4-phenylbutanoyl homoserine lactone inhibits the binding of OHHL in E. coli containing LuxR and also antagonizes LuxR in V. fischeri (12,37). 3-Oxo-C 12 -(2-aminophenol) was found to inhibit GFP production in a Pseudomonas aeruginosa strain constructed to express GFP in its quorum sensing circuit (39), as well as TraR in Agrobacterium tumefaciens (13).…”

Section: Discussionmentioning

confidence: 99%

Secondary Metabolites Produced by the Marine Bacterium Halobacillus salinus That Inhibit Quorum Sensing-Controlled Phenotypes in Gram-Negative Bacteria

Teasdale

Liu

Wallace

et al. 2009

Appl Environ Microbiol

171

114

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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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“…The docking results were somehow surprising to us because many reports have documented the importance of the chirality at the C3 position for AHL autoinducers in activating QS-mediated processes. 13,33,34 In this report we show that 3-aminooxazolidinone that lacks a C3 chirality could still bind to some LuxR-type receptors and is as potent, in binding to LasR, as the native 3-oxo-C12 HSL.…”

Section: -15mentioning

confidence: 97%

3-Aminooxazolidinone AHL analogs as hydrolytically-stable quorum sensingagonists in Gram-negative bacteria

et al. 2015

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Synthetic molecules that modulate quorum sensing, QS, in bacteria have great potential for use in synthetic biology applications as well as acting as anti-virulence and anti-biofilm agents. Acylhomoserine lactone (AHL)-based autoinducer analogs have been extensively developed as QS modulators but these suffer from both chemical and enzymatic degradations. Here, we reveal that 3-aminooxazolidinone acylhomoserine lactone analogs are hydrolytically stable and are as potent in activating LuxR-type receptors.Docking analysis revealed that 3-oxo-C12-3-aminooxazolidinone docked in LasR of P. aeruginosa, making similar interactions with the protein's active-site residues to the native ligand, 3-oxo-C12 HSL. Experimentally, 3-oxo-C12-3-aminooxazolidinone was equally as potent as the natural ligand in inducing bioluminescence in E. coli carrying a bioluminescent gene that was under the control of LasR. In C. violaceum CV026, the 3-aminooxazolidinone analogs could also modulate pigment (violacein) formation, albeit this time not as potent as the natural AHL ligands.

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Comparative Analyses of N‐Acylated Homoserine Lactones Reveal Unique Structural Features that Dictate Their Ability to Activate or Inhibit Quorum Sensing

Cited by 100 publications

References 35 publications

Quorum Sensing Interference and Structural Variation of Quorum Sensing Mimics in Australian Soft Coral

Quorum Sensing Interference and Structural Variation of Quorum Sensing Mimics in Australian Soft Coral

Secondary Metabolites Produced by the Marine Bacterium Halobacillus salinus That Inhibit Quorum Sensing-Controlled Phenotypes in Gram-Negative Bacteria

3-Aminooxazolidinone AHL analogs as hydrolytically-stable quorum sensingagonists in Gram-negative bacteria

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