Quorum Sensing Inhibition: Targeting Chemical Communication in Gramnegative Bacteria

Persson, Tobias; Givskov, Michael; Nielsen, Jakob Blæsbjerg

doi:10.2174/092986705774933425

Cited by 88 publications

(61 citation statements)

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“…As a result of the specific binding between signal receptor proteins and their signal molecules, competitive inhibitors that interfere with their interactions have been suggested as potential QS inhibitors that can reduce the formation of harmful biofilms and also increase the susceptibility of many pathogenic microbes to antibiotic treatment as well (Kim et al, 2008;Persson et al, 2005;Tateda et al, 2001). However, a biochemical assay for screening QS inhibitors based on the binding affinity between receptor proteins and their signal molecules was not available until recently because of the difficulty in isolating the signal receptor proteins, including LasR and TraR, which are produced as a complex that is tightly associated with their cognate signal molecules (Kiratisin et al, 2002;Schuster et al, 2004).…”

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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“…Evidence now shows that QSIs targeting LasR can attenuate the pathogenicity of P. aeruginosa (17,25,26). QSI compounds have been obtained from natural sources or by synthesis of AHL analogues or by screening random libraries (reviewed in Ref.…”

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confidence: 99%

Molecular Insights into Quorum Sensing in the Human Pathogen Pseudomonas aeruginosa from the Structure of the Virulence Regulator LasR Bound to Its Autoinducer

Bottomley

Muraglia

Bazzo

et al. 2007

Journal of Biological Chemistry

366

476

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Many Gram-negative bacteria communicate via molecules called autoinducers to coordinate the activities of their populations. Such communication is termed quorum sensing and can regulate pathogenic virulence factor production and antimicrobial resistance. The quorum sensing system of Pseudomonas aeruginosa is currently the most intensively researched, because this bacterium is an opportunistic human pathogen annually responsible for the death of thousands of cystic fibrosis sufferers and many other immunocompromised individuals. Quorum sensing inhibitors can attenuate the pathogenicity of P. aeruginosa. Here we present the crystal structure of the P. aeruginosa LasR ligand-binding domain bound to its autoinducer 3-oxo-C 12 -acylhomoserine lactone. The structure is a symmetrical dimer, with each monomer exhibiting an ␣-␤-␣ fold similar to the TraR and SdiA quorum sensing proteins of Agrobacterium tumefaciens and Escherichia coli. The structure was determined up to 1.8-Å resolution and reveals the atomic interactions between LasR and its autoinducer. The monomer structures of LasR, TraR, and SdiA are comparable but display differences in their quaternary organization. Inspection of their binding sites shows some unexpected variations resulting in quite different conformations of their bound autoinducers. We modeled interactions between LasR and various quorum sensing inhibitors, yielding insight into their possible mechanisms of action. The structure also provides a platform for the optimization, or de novo design, of quorum sensing inhibitors.Evolution has endowed bacteria with a wide variety of diffusible chemical signals that are used for communication both within and between species. The most common form of intercellular communication in Gram-negative bacteria is "quorum sensing," so named because the bacteria initiate coordinated activities only when a "quorum" population density is reached (1). This synchronization of individual behavior into cooperative group activity can have many different benefits, e.g. to produce virulence factors only when the bacterial population is sufficiently dense to survive host immune responses (2-4).The first quorum sensing system described was that of Vibrio fischeri, a symbiont of the Hawaiian bobtail squid (5, 6). The squid has a "light organ" wherein it provides nutrition for V. fischeri. Upon reaching high population density the bacteria produce bioluminescence enabling the squid to cancel its own shadow and thereby avoid predation (7). The quorum sensing mechanism triggering bioluminescence depends on the bacterial synthase LuxI, which constitutively produces a signal molecule, an acylhomoserine lactone (acyl-HSL or AHL), 2 the autoinducer. The AHL diffuses through the bacterial envelope, and, upon reaching a threshold concentration, the AHL binds and activates its receptor LuxR, a transcriptional activator of the luciferase operon (1). Many different Gram-negative bacteria have now been shown to use quorum sensing systems composed of LuxI/LuxR homologues and AHL autoinduc...

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“…For example, macrolides such as azithromycin, which inhibit N-acylhomoserine lactone-mediated quorum sensing but do not inhibit the growth of Pseudomonas aeruginosa, are known to efficiently decrease the symptoms of cystic fibrosis and diffuse panbronchiolitis (57,58). Furthermore, a number of other studies have revealed inhib-itors targeting N-acylhomoserine lactone-mediated quorum sensing of gram-negative bacteria (26,43,50,54,55). In the case of gram-positive pathogens, quorum-sensing inhibitors have been investigated with staphylococci, which have a wellknown regulatory system designated agr (32,41).…”

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confidence: 99%

Siamycin Attenuates fsr Quorum Sensing Mediated by a Gelatinase Biosynthesis-Activating Pheromone in Enterococcus faecalis

Nakayama¹,

Tanaka²,

Kariyama

et al. 2007

J Bacteriol

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The expression of two Enterococcus faecalis virulence-related proteases, gelatinase (GelE) and serine protease (SprE), is positively regulated by a quorum-sensing system encoded by the fsr gene cluster. In this system, E. faecalis secretes an autoinducing peptide, gelatinase biosynthesis-activating pheromone (GBAP), which triggers the FsrC-FsrA two-component regulatory system controlling the expression of two transcripts, fsrBDC and gelE-sprE. In the present study, we screened actinomycete metabolites for inhibitors of fsr quorum sensing. E. faecalis was cultured with each actinomycete culture supernatant tested, and the production of gelatinase and the production of GBAP were examined using the first screening and the second screening, respectively. Culture supernatant of Streptomyces sp. strain Y33-1 had the most potent inhibitory effect on both gelatinase production and GBAP production without inhibiting E. faecalis cell growth. The inhibitor in the culture supernatant was identified as a known peptide antibiotic, siamycin I. Siamycin I inhibited both gelatinase production and GBAP production at submicromolar concentrations, and it inhibited E. faecalis cell growth at concentrations above micromolar concentrations. Quantitative analysis of fsrBDC and gelE-sprE transcripts revealed that siamycin I suppressed the expression of both transcripts at a sublethal concentration. Siamycin I attenuated gelatinase production even when an overdose of GBAP was exogenously added to the culture. These results suggested that siamycin I inhibited the GBAP signaling via the FsrC-FsrA two-component regulatory system in a noncompetitive manner. The sublethal concentrations of siamycin I also attenuated biofilm formation. Treatment with siamycin could be a novel means of treating enterococcal infections.Enterococcus faecalis is a gram-positive intestinal commensal of humans and other animals, but it sometimes causes opportunistic infections, including urinary tract, bloodstream, and wound infections, endophtalmitis, and endocarditis (22). Notably, in the past two decades, nosocomial infections caused by multiple-antibiotic-resistant or vancomycin-resistant E. faecalis have become a serious clinical problem (6,33,36,49).Besides cytolysin, which is lethal by itself for a broad range of prokaryotic and eukaryotic cells (10), several virulence-related factors have been found in E. faecalis, including aggregation substance (Agg), enterococcal surface protein (Esp), and two extracellular proteases, gelatinase (GelE) and serine protease (SprE) (35, 59). These factors have been thought to act synergistically to enhance virulence by facilitating colonization, translocation, and biofilm formation (8,16,23,28,34,35,52,60,62,65). GelE and SprE are encoded in an operon, gelE-sprE, whose expression is positively regulated by a quorum-sensing system encoded by the fsr locus (45,46). Several in vivo studies using animal or nematode models have shown that the fsr system contributes to virulence (17,19,37,46,53).The fsr locus is comprised of four ...

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Quorum Sensing Inhibition: Targeting Chemical Communication in Gramnegative Bacteria

Cited by 88 publications

References 0 publications

Inhibitors of the Pseudomonas aeruginosa quorum‐sensing regulator, QscR

Inhibitors of the Pseudomonas aeruginosa quorum‐sensing regulator, QscR

Molecular Insights into Quorum Sensing in the Human Pathogen Pseudomonas aeruginosa from the Structure of the Virulence Regulator LasR Bound to Its Autoinducer

Siamycin Attenuates fsr Quorum Sensing Mediated by a Gelatinase Biosynthesis-Activating Pheromone in Enterococcus faecalis

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