Synthetic ligands that activate and inhibit a quorum-sensing regulator in Pseudomonas aeruginosa

Mattmann, Margrith E.; Geske, Grant D.; Worzalla, Gregory A.; Chandler, Josephine R.; Sappington, Kaia J.; Greenberg, E. Peter; Blackwell, Helen E.

doi:10.1016/j.bmcl.2007.11.095

Cited by 66 publications

(88 citation statements)

References 20 publications

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“…Furthermore, the apoQscR could recombine with 3OC12-HSL to form an active QscR-signal complex that recovers the ability to bind to its target promoter in vitro. By using purified QscR proteins, the screening of QS inhibitors with a limited number of chemicals has also been attempted (Mattmann et al, 2008). This has become an important breakthrough that enables the development of an in vitro biochemical assay for screening of QS inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Inhibitors of the Pseudomonas aeruginosa quorum‐sensing regulator, QscR

Liu

Lee

Kim

et al. 2010

Biotech & Bioengineering

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QscR is a quorum-sensing (QS) signal receptor that controls expression of virulence genes in the prevalent opportunistic pathogen, Pseudomonas aeruginosa. Unlike the previously reported LuxR-type QS receptor proteins, that is, LasR and TraR, QscR can be obtained as an apo-protein that can reversibly form an active complex in vitro with its cognate signal molecule, 3-oxododecanoyl-homoserine lactone (3OC12-HSL), and subsequently bind to target promoter DNA sequences. To search for potential QS inhibitors, an in vitro gel retardation assay was developed using the purified QscR. Both the in vitro assay and the in vivo cellbased assay using QscR-overproducing recombinant strains were applied in the screening process. Furanones were chosen for testing the activity as QS inhibitors because they have been reported to strongly inhibit expression of QS-related genes in Agrobacterium tumefaciens. Among more than a hundred furanones tested, three compounds showed strong and dose-dependent inhibitory effects on QscR in both assays. One compound in particular, designated as F2, could completely inhibit the 3OC12-HSL-dependent QscR activity in vitro at a concentration of 50-fold molar excess over 3OC12-HSL. However, with the furanones F3 and F4, which are structurally similar to F2 but with a nitro group instead of the amine moiety, significantly decreased activities were observed. These results suggest that (i) the in vitro assay is a sensitive and reliable tool for screening QS inhibitors, and (ii) furanones are potentially important QS inhibitors for many LuxR-type receptor proteins.

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Section: Introductionmentioning

confidence: 99%

Inhibitors of the Pseudomonas aeruginosa quorum‐sensing regulator, QscR

Liu

Lee

Kim

et al. 2010

Biotech & Bioengineering

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“…Inhibitors 1 and 2 are modified from 3OC12HSL by McInnis and Blackwell (2011); inhibitor 3 is a furanone described in Hentzer et al (2002) and Wu et al (2004); inhibitor 4 is patulin described in Rasmussen et al (2005); inhibitors 5 and 6 are from a chemical library described in Muh et al (2006b); inhibitor 7 is a triphenyl derivative from Muh et al (2006a); inhibitor 8 is C10-acylcyclopentylamine from Ishida et al (2007); inhibitor 9 is solenopsin from Park et al (2008); and compound 10 is propanoyl homoserine lactone from Mattmann et al (2008). its targets is rhlI, leading to autoinduction of this second QS circuit.…”

Section: Quorum Sensing and Virulencementioning

confidence: 99%

“…For example, a small molecule library was screened for agonists and antagonists of QscR, which, as described, influences both the LasI/LasR and RhlI/RhlR systems Mattmann et al 2008Mattmann et al , 2011Amara et al 2009;Liu et al 2010). By agonizing QscR, it could be possible to diminish the overall QS response and thus prevent or delay expression of virulence factors.…”

Section: P Aeruginosa Qs As a Therapeutic Targetmentioning

confidence: 99%

Bacterial Quorum Sensing: Its Role in Virulence and Possibilities for Its Control

Rutherford

Bassler

2012

Cold Spring Harbor Perspectives in Medicine

1,569

1,258

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Quorum sensing is a process of cell-cell communication that allows bacteria to share information about cell density and adjust gene expression accordingly. This process enables bacteria to express energetically expensive processes as a collective only when the impact of those processes on the environment or on a host will be maximized. Among the many traits controlled by quorum sensing is the expression of virulence factors by pathogenic bacteria. Here we review the quorum-sensing circuits of Staphylococcus aureus, Bacillus cereus, Pseudomonas aeruginosa, and Vibrio cholerae. We outline these canonical quorum-sensing mechanisms and how each uniquely controls virulence factor production. Additionally, we examine recent efforts to inhibit quorum sensing in these pathogens with the goal of designing novel antimicrobial therapeutics.

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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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Synthetic ligands that activate and inhibit a quorum-sensing regulator in Pseudomonas aeruginosa

Cited by 66 publications

References 20 publications

Inhibitors of the Pseudomonas aeruginosa quorum‐sensing regulator, QscR

Inhibitors of the Pseudomonas aeruginosa quorum‐sensing regulator, QscR

Bacterial Quorum Sensing: Its Role in Virulence and Possibilities for Its Control

Crystal structure of QscR, aPseudomonas aeruginosaquorum sensing signal receptor

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