Mechanisms and Synthetic Modulators of AHL-Dependent Gene Regulation

Stevens, Ann M.; Queneau, Yves; Soulère, Laurent; Bodman, Susanne von; Doutheau, Alain

doi:10.1021/cr100064s

Cited by 85 publications

(92 citation statements)

References 166 publications

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“…Analogues have been found that exhibit a range of different activities, including no activity, pure agonism or pure antagonism, partial agonism, and synergistic agonism (167,(170)(171)(172). The different AHL analogues tested to date and their specific activities against the various receptor proteins are too numerous to report here in detail, so for a more comprehensive and specific discussion of these molecules we refer the reader to other recently published reviews (173,174). There are some general findings of these investigations, however, that we have chosen to discuss below, as well as several specific examples of AHL receptor antagonists that show promise for the future development of analogue-based QSI strategies.…”

Section: Inhibition Of Signal Detection Synthetic Signal Analogues Anmentioning

confidence: 99%

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

LaSarre

Federle

2013

Microbiol Mol Biol Rev

693

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 Anmentioning

confidence: 99%

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

LaSarre

Federle

2013

Microbiol Mol Biol Rev

693

556

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“…AHL-dependent quorum sensing activates virulence in many plant and animal pathogens, and the LuxR family of AHL receptors has been a target for therapeutic drug development (6)(7)(8)(9)(10)(11)(12). Unfortunately, there is a paucity of structural data for members of the LuxR family of AHL-responsive transcription factors (13).…”

mentioning

confidence: 99%

Crystal structure of QscR, aPseudomonas aeruginosaquorum sensing signal receptor

Lintz

Oinuma

Wysoczynski

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

113

131

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Acyl-homoserine lactone (AHL) quorum sensing controls gene expression in hundreds of Proteobacteria including a number of plant and animal pathogens. Generally, the AHL receptors are members of a family of related transcription factors, and although they have been targets for development of antivirulence therapeutics there is very little structural information about this class of bacterial receptors. We have determined the structure of the transcription factor, QscR, bound to N-3-oxo-dodecanoyl-homoserine lactone from the opportunistic human pathogen Pseudomonas aeruginosa at a resolution of 2.55 Å. The ligand-bound QscR is a dimer with a unique symmetric “cross-subunit” arrangement containing multiple dimerization interfaces involving both domains of each subunit. The QscR dimer appears poised to bind DNA. Predictions about signal binding and dimerization contacts were supported by studies of mutant QscR proteins in vivo. The acyl chain of the AHL is in close proximity to the dimerization interfaces. Our data are consistent with an allosteric mechanism of signal transmission in the regulation of DNA binding and thus virulence gene expression.

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“…LuxR and LuxS receptors) to induce the expression of virulence genes. Given the central role of QS systems in bacterial pathogenesis, many efforts have focused on interfering with these pathways (recently reviewed in [43][44][45][46][47][48]). Quorum quenching is a term that has been used to describe 'any approach that interferes with microbial QS signalling' [49].…”

Section: Targeting Communication Systemsmentioning

confidence: 99%