N‐Sulfonyl Homoserine Lactones as Antagonists of Bacterial Quorum Sensing.

Castang, Sandra; Chantegrel, Bernard; Deshayes, Christian; Dolmazon, René; Gouet, Patrice; Haser, R.; Reverchon, Sylvie; Nasser, William; Hugouvieux‐Cotte‐Pattat, Nicole; Doutheau, Alain

doi:10.1002/chin.200505177

Cited by 27 publications

(50 citation statements)

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“…This is in agreement with studies demonstrating that even minor changes in the length or substituents of the acyl tail, which contributes to the binding affinity between the receptor and the ligand (11,166,(194)(195)(196), can have large effects on its activity (11,170,197). Alteration of the chirality of the lactone ring or substitutions of part or all of the lactone head group can also alter the activity of a given molecule for a given AHL receptor (11, 118, 165-167, 196, 197), likely because of important conserved intermolecular hydrogen bonds between the AHL lactone head group and the ligand-binding pockets of AHL receptors (175)(176)(177)(178)(179)(180).…”

Section: Inhibition Of Signal Detection Synthetic Signal Analogues Ansupporting

confidence: 92%

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

LaSarre

Federle

2013

Microbiol Mol Biol Rev

690

556

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SUMMARY Cell-cell communication, or quorum sensing, is a widespread phenomenon in bacteria that is used to coordinate gene expression among local populations. Its use by bacterial pathogens to regulate genes that promote invasion, defense, and spread has been particularly well documented. With the ongoing emergence of antibiotic-resistant pathogens, there is a current need for development of alternative therapeutic strategies. An antivirulence approach by which quorum sensing is impeded has caught on as a viable means to manipulate bacterial processes, especially pathogenic traits that are harmful to human and animal health and agricultural productivity. The identification and development of chemical compounds and enzymes that facilitate quorum-sensing inhibition (QSI) by targeting signaling molecules, signal biogenesis, or signal detection are reviewed here. Overall, the evidence suggests that QSI therapy may be efficacious against some, but not necessarily all, bacterial pathogens, and several failures and ongoing concerns that may steer future studies in productive directions are discussed. Nevertheless, various QSI successes have rightfully perpetuated excitement surrounding new potential therapies, and this review highlights promising QSI leads in disrupting pathogenesis in both plants and animals.

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Section: Inhibition Of Signal Detection Synthetic Signal Analogues Ansupporting

confidence: 92%

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

LaSarre

Federle

2013

Microbiol Mol Biol Rev

690

556

View full text Add to dashboard Cite

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“…As the size difference of the cyclic alkyls and the aryl substituents is minimal, it is hypothesized that the aryl compounds can interact with aromatic amino acid residues in the LuxR protein, preventing normal activation (Reverchon et al, 2002). The QSI effect of the aryl AHLs can be further enhanced by replacing the C-1 carbonyl group of the side chain with a sulphonyl group (Castang et al, 2004).…”

Section: Interference With the Signal Receptormentioning

confidence: 99%

Quorum sensing inhibitors: a bargain of effects

2006

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Many opportunistic pathogenic bacteria rely on quorum sensing (QS) circuits as central regulators of virulence expression. In Pseudomonas aeruginosa, QS-regulated gene expression contributes to the formation and maintenance of biofilms and their tolerance to conventional antimicrobials and the host innate immune system. Therefore, QS is an obvious target for a novel class of antimicrobial drugs which would function to efficiently block reception of the cognate QS signals in vivo, and thereby be capable of inducing chemical attenuation of pathogens. As QS is not directly involved in processes essential for growth of the bacteria, inhibition of QS does not impose harsh selective pressure for development of resistance as with antibiotics. Numerous chemical libraries of both natural and synthetic origin have been screened and several QS-inhibitory compounds have been identified. In animal pulmonary infection models, such inhibitors have proven able to significantly improve clearing of the infecting bacteria and reduce mortality. In addition, several enzymes that are able to inactivate the bacterial QS signal molecules have been identified. This inactivation leads to blockage of QS-mediated virulence of plant pathogens in several models. Quorum sensingBacteria are social organisms capable of interacting with each other and their surroundings. Particularly well described is the ability to coordinate gene expression in accordance with population density, a process termed quorum sensing (QS) (Fuqua et al., 1994). In Gram-negative bacteria this is achieved by production and reception of diffusible signal molecules in the form of acylhomoserine lactones (AHLs) (Fig. 1). The signal molecules are produced by an AHL synthase encoded by homologues of the AHL synthase gene luxI, which was first identified in Vibrio fischeri (Engebrecht & Silverman, 1984). At low population densities, luxI is constitutively expressed at a low, basal level. Hence, the AHLs accumulate in the surroundings. The LuxR family of receptor/response regulator proteins perceives the AHLs. At a certain threshold concentration of AHL, the signal molecule forms a complex with the receptor protein, which becomes activated. The activated receptor-signal complex in turn forms dimers or multimers with other activated LuxR-AHL complexes. These dimers or multimers function as transcriptional regulators controlling expression of QS-regulated target genes. The QS paradigm states that transcription of QS target genes is activated at a certain population density (which is proportional to the AHL concentration) known as the 'quorum size' -the number of bacteria required to activate the QS system (Eberl, 1999;Fuqua et al., 1994;Salmond et al., 1995;Parsek et al., 1999). In Pseudomonas aeruginosa, however, recent research has shown that each individual QS-regulated gene possesses its own specific quorum size. There is not a single population density at which all QS genes are activated; rather, different genes are activated at different population densities Wagner et al....

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“…[9][10][11][12][13][14][15][16][17][18][19] Structural modifications to the lactone ring, including inversion of stereochemistry, [20] and replacement of the lactone with different carbo-or heterocycles [9][10][11]17,[21][22][23] have been examined to a lesser degree. Four of the most effective AHL-derived antagonists of TraR, LasR, or LuxR reported to date are shown in Scheme 1: the C 7 AHL 4 active against TraR, [13] the 3-oxo-phenylbutanoyl-and phenylbutanoyl HLs (5 and 6) active against LuxR, [14] and the 2-aminophenol analogue of OdDHL 7 active against LasR.…”

Section: Oxo-octanoyl)-l-homoserine Lactone (Oohl 1) and Trar In Thementioning

confidence: 99%

“…[3] Several of the sulfonyl compounds in library A (A9-A14) were reported by Castang et al to inhibit LuxR activity at a low to moderate level (in a heterologous E. coli LuxR reporter strain), with activity maximal at a five-carbon (six atom) acyl chain length (i.e., A10). [15] Collectively, however, these ligands have not been examined in the three bacterial strains utilized in this study. Consequently, library A was designed to provide important benchmark data for the comparison of antagonistic and agonistic ligand activities between the strains…”

Section: Design Of Ahl Library Amentioning

confidence: 99%

“…[17] (We note, however, that many synthetic AHLs have been tested in racemic form, or their reported stereochemistry was not explicit, which adds additional complexity to this analysis. [9][10][11][13][14][15][16]) Lastly, the roles of acyl group aromaticity and spacer length on ligand activity, specifically in our antagonists 8 and 9, were unknown.…”

Section: Design Of Ahl Library Bmentioning

confidence: 99%

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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

et al. 2008

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Bacterial quorum sensing is mediated by low molecular-weight signals and plays a critical role in both the pathogenesis of infectious disease and beneficial symbioses. There is significant interest in the development of synthetic ligands that can intercept bacterial quorum sensing signals and modulate these outcomes. Here, we report the design and comparative analysis of the effects of ~ 90 synthetic N-acylated homoserine lactones (AHLs) on quorum sensing in three Gram negative bacterial species and a critical examination of the structural features of these ligands that dictate agonistic and antagonistic activity, and selectivity for different R protein targets. These studies have revealed the most comprehensive set of structure-activity relationships to date that direct AHL-mediated quorum sensing and a new set of chemical probes with which to study this complex signaling process. Furthermore, this work provides a foundation on which to design next-generation quorum sensing modulators with improved activities and selectivities.

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N‐Sulfonyl Homoserine Lactones as Antagonists of Bacterial Quorum Sensing.

Cited by 27 publications

References 1 publication

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

Quorum sensing inhibitors: a bargain of effects

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

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