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PubMed2003

Synthesis of furanone-based natural product analogues with quorum sensing antagonist activity.

The synthesis of 5- and 3-(1'-hydroxyalkyl)-substituted 5H-furan-2-ones 4a-d and 8a-d as well as 5-alkylidene-5H-furan-2-ones 5a-d is described. A study of the structure-activity relationship of these furanone-based natural product analogues towards two different quorum sensing systems is reported. Although the synthesized compounds are not as potent quorum sensing inhibitors as some natural counterparts and a synthetic analogue hereof, interesting structure-activity relationships are seen.

Bacterial Proteins↗

PubMed2003

Regulation of Vibrio vulnificus virulence by the LuxS quorum-sensing system.

Vibrio vulnificus is a halophilic estuarine bacterium that causes fatal septicaemia and necrotizing wound infections. We tested whether V. vulnificus produces signalling molecules (autoinducer 1 and/or 2) stimulating Vibrio harveyi quorum-sensing system 1 and/or 2. Although there was no evidence for signalling system 1, we found that V. vulnificus produced a signalling activity in the culture supernatant that induced luminescence expression in V. harveyi through signalling system 2. Maximal autoinducer 2 (AI-2) activity was observed during mid-exponential to early stationary phase and disappeared in the late stationary phase when V. vulnificus was grown in heart infusion broth containing 2.5% NaCl. V. vulnificus showed increased signalling activity when it was cultured in the presence of glucose (0.5%) and at low pH (pH 6.0). From a cosmid library of V. vulnificus type strain ATCC 29307, we have identified the AI-2 synthase gene (luxSVv) showing 80% identity with that of V. harveyi (luxSVh) at the amino acid level. To investigate the pathogenic role of luxSVv, a deletion mutant of the clinical isolate V. vulnificus MO6-24/O was constructed. The luxSVv mutant showed a significant delay in protease production and an increase in haemolysin production. The decreased protease and increased haemolysin activities were restored to the isogenic wild-type level by complementation with the wild-type luxSVv allele. The change in phenotypes was also complemented by logarithmic phase spent media produced by the wild-type bacteria. Transcriptional activities of the haemolysin gene (vvhA) and protease gene (vvpE) were also observed in the mutant using chromosomal PvvhA::lacZ and PvvpE::lacZ transcriptional reporter constructs: transcription of vvhA was increased and of vvpE decreased by the mutation. The mutation resulted in an attenuation of lethality to mice. Intraperitoneal LD50 of the luxSVv mutant increased by 10- and 750-fold in ferric ammonium citrate-non-overloaded and ferric ammonium citrate-overloaded mice respectively. The time required for the death of mice was also significantly delayed in the luxSVv mutant. Cytotoxic activity of the organism against HeLa cells, measured by lactate dehydrogenase (LDH) release assay, was also decreased significantly by the mutation. Taken together, the V. vulnificus LuxS quorum-sensing system seems to play an important role in co-ordinating the expression of virulence factors.

Amino Acid Sequence↗

PubMed1998

Production of acyl-homoserine lactone quorum-sensing signals by gram-negative plant-associated bacteria.

Many gram-negative bacteria regulate expression of specialized gene sets in response to population density. This regulatory mechanism, called autoinduction or quorum-sensing, is based on the production by the bacteria of a small, diffusible signal molecule called the autoinducer. In the most well-studied systems the autoinducers are N-acylated derivatives of L-homoserine lactone (acyl-HSL). Signal specificity is conferred by the length, and the nature of the substitution at C-3, of the acyl side-chain. We evaluated four acyl-HSL bioreporters, based on tra of Agrobacterium tumefaciens, lux of Vibrio fischeri, las of Pseudomonas aeruginosa, and pigment production by Chromobacterium violaceum, for their ability to detect sets of 3-oxo acyl-HSLs, 3-hydroxy acyl-HSLs, and alkanoyl-HSLs with chain lengths ranging from C4 to C12. The traG::lacZ fusion reporter from the A. tumefaciens Ti plasmid was the single most sensitive and versatile detector of the four. Using this reporter, we screened 106 isolates representing seven genera of bacteria that associate with plants. Most of the Agrobacterium, Rhizobium, and Pantoea isolates and about half of the Erwinia and Pseudomonas isolates gave positive reactions. Only a few isolates of Xanthomonas produced a detectable signal. We characterized the acyl-HSLs produced by a subset of the isolates by thin-layer chromatography. Among the pseudomonads and erwinias, most produced a single dominant activity chromatographing with the properties of N-(3-oxo-hexanoyl)-L-HSL. However, a few of the erwinias, and the P. fluorescens and Ralstonia solanacearum isolates, produced quite different signals, including 3-hydroxy forms, as well as active compounds that chromatographed with properties unlike any of our standards. The few positive xanthomonas, and almost all of the agrobacteria, produced small amounts of a compound with the chromatographic properties of N-(3-oxo-octanoyl)-L-HSL. Members of the genus Rhizobium showed the greatest diversity, with some producing as few as one and others producing as many as seven detectable signals. Several isolates produced extremely nonpolar compounds indicative of very long acyl side-chains. Production of these compounds suggests that quorum-sensing is common as a gene regulatory mechanism among gram-negative plant-associated bacteria.

4-Butyrolactone↗

PubMed2000

How Delisea pulchra furanones affect quorum sensing and swarming motility in Serratia liquefaciens MG1.

Halogenated furanones produced by the benthic marine macroalga Delisea pulchra inhibit swarming motility of Serratia liquefaciens MG1. This study demonstrates that exogenously added furanones control transcription of the quorum sensing regulated gene swrA in competition with the cognate signal molecule N:-butanoyl-L-homoserine lactone. This in turn results in reduced production of the surface-active compound serrawettin W2, which is crucial for surface translocation of the differentiated swarm cells. It is demonstrated that furanones interfere with interspecies communication during swarming of mixed cultures and that the mode of interference in quorum-sensing control and interspecies communication is not through inhibition of autoinducer synthesis.

4-Butyrolactone↗

PubMed2002

Virulence effect of Enterococcus faecalis protease genes and the quorum-sensing locus fsr in Caenorhabditis elegans and mice.

The expression of two Enterococcus faecalis extracellular virulence-related proteins, gelatinase (GelE) and serine protease (SprE), has been shown to be positively regulated by the fsr quorum-sensing system. We recently developed a novel system for studying E. faecalis pathogenicity that involves killing of the nematode worm Caenorhabditis elegans and showed that an E. faecalis fsrB mutant (strain TX5266) exhibited attenuated killing. We explore here the role of the fsr/gelE-sprE locus in pathogenicity by comparing results obtained in the nematode system with a mouse peritonitis model of E. faecalis infection. Insertion mutants of fsrA (TX5240) and fsrC (TX5242), like fsrB (TX5266), were attenuated in their ability to kill C. elegans. A deletion mutant of gelE (TX5264) and an insertion mutant of sprE (TX5243) were also attenuated in C. elegans killing, although to a lesser extent than the fsr mutants. Complementation of fsrB (TX5266) with a 6-kb fragment containing the entire fsr locus restored virulence in both the nematode and the mouse peritonitis models. The fsr mutants were not impaired in their ability to colonize the nematode intestine. These data show that extracellular proteases and the quorum-sensing fsr system are important for E. faecalis virulence in two highly divergent hosts: nematodes and mice.

Animals↗

PubMed2003

A constitutively active variant of the quorum-sensing regulator LuxO affects protease production and biofilm formation in Vibrio cholerae.

Vibrio cholerae normally inhabits aquatic habitats but can cause a severe diarrheal illness in humans. Its arsenal of virulence factors includes a secreted hemagglutinin (HA) protease. An HA protease-deficient mutant of V. cholerae was isolated and designated E7946 mpc. E7946 mpc was found to contain a point mutation in the luxO quorum-sensing regulator. In accordance with this finding, E7946 mpc exhibits a defect in quorum sensing. The mutant luxO allele [luxO(Con)] produces a protein with a leucine-to-glutamine substitution at amino acid 104. Transfer of the luxO(Con) allele to an otherwise wild-type background was sufficient to eliminate HA protease expression; conversely, deletion of luxO(Con) from E7946 mpc restored protease activity. We demonstrate that LuxO(Con) constitutively represses the transcription of hapR, an essential positive regulator of HA protease. Interestingly, strains harboring luxO(Con) form enhanced biofilms, and enhanced biofilm formation does not appear to be dependent on reduced HA protease expression. Taken together, the results confirm the role of LuxO as a central "switch" that coordinately regulates virulence-related phenotypes such as protease production and biofilm formation.

Bacterial Proteins↗

PubMed2002

Quorum sensing: an emerging target for antibacterial chemotherapy?

The emergence of bacterial strains exhibiting resistance to multiple antibiotic classes poses a major threat to medicine and public health. This has been compounded over the last few decades by the failure of drug discovery programmes to provide new broad spectrum antibacterials with novel modes of action. As a consequence, there is renewed interest in antibacterial targets which disrupt the capacity of pathogenic bacteria to cause infection by attenuating virulence. In this respect, one crucial feature of almost all bacterial infections is that the pathogen must attain a critical cell population density sufficient to overwhelm the host defences. Many pathogens are now known to regulate diverse physiological processes, including virulence, in a cell density dependent manner through cell-cell communication. This phenomenon, which relies upon the interaction of a diffusible signal molecule with a sensor kinase or response regulator, has become known as 'quorum sensing'. This review considers the molecular basis of quorum sensing and whether it constitutes a potential therapeutic target for the design of small molecule antagonists capable of controlling infection by attenuating adaptation to the host environment.

4-Butyrolactone↗

PubMed2006

Linking bacteriophage infection to quorum sensing signalling and bioluminescent bioreporter monitoring for direct detection of bacterial agents.

AIM: To incorporate into the lambda phage genome, a luxI-based acyl-homoserine lactone (AHL) synthase genetic construct and exploit the autoamplified power of quorum sensing to translate a phage infection event into a chemical signature detectable by a lux-based bioluminescent bioreporter, with focus towards facile detection of microbial pathogens. METHODS AND RESULTS: The luxI gene from Vibrio fischeri was inserted into the lambda phage genome to construct a model phage-based biosensor system for the general detection of Escherichia coli. The AHL signalling molecules synthesized upon phage infection are detected by an AHL-specific bioluminescent bioreporter based on the luxCDABE gene cassette of V. fischeri. The assay generates target-specific visible light signals with no requisite addition of extraneous substrate. This binary reporter system was able to autonomously respond to lambda phage infection events at target E. coli concentrations ranging from 1 x 10(8) to 1 CFU ml(-1) within 1.5-10.3 h, respectively, in pure culture. When assayed against artificially contaminated lettuce leaf washings, detection within an E. coli inoculum range from 1 x 10(8) to 130 CFU ml(-1) was achieved within 2.6-22.4 h, respectively. CONCLUSIONS: The initial feasibility of binary phage-based reporter assays indicates that quorum sensing can be used to translate a phage infection event into an autoamplified chemical signature. SIGNIFICANCE AND IMPACT OF STUDY: With further modification, binary phage-based reporter assays may be capable of rapidly and cost effectively detecting pathogenic agents at very low population densities.

4-Butyrolactone↗

PubMed2005

Sociomicrobiology: the connections between quorum sensing and biofilms.

In the past decade, significant debate has surrounded the relative contributions of genetic determinants versus environmental conditions to certain types of human behavior. While this debate goes on, it is with a certain degree of irony that microbiologists studying aspects of bacterial community behavior face the same questions. Information regarding two social phenomena exhibited by bacteria, quorum sensing and biofilm development, is reviewed here. These two topics have been inextricably linked, possibly because biofilms and quorum sensing represent two areas in which microbiologists focus on social aspects of bacteria. We will examine what is known about this linkage and discuss areas that might be developed. In addition, we believe that these two aspects of bacterial behavior represent a small part of the social repertoire of bacteria. Bacteria exhibit many social activities and they represent a model for dissecting social behavior at the genetic level. Therefore, we introduce the term 'sociomicrobiology'.

Adaptation, Physiological↗

PubMed2005

Cell cycle dynamics and quorum sensing in Candida albicans chlamydospores are distinct from budding and hyphal growth.

The regulation of morphogenesis in the human fungal pathogen Candida albicans is under investigation to better understand how the switch between budding and hyphal growth is linked to virulence. Therefore, in this study we examined the ability of C. albicans to undergo a distinct type of morphogenesis to form large thick-walled chlamydospores whose role in infection is unclear, but they act as a resting form in other species. During chlamydospore morphogenesis, cells switch to filamentous growth and then develop elongated suspensor cells that give rise to chlamydospores. These filamentous cells were distinct from true hyphae in that they were wider and were not inhibited by the quorum-sensing factor farnesol. Instead, farnesol increased chlamydospore production, indicating that quorum sensing can also have a positive role. Nuclear division did not occur across the necks of chlamydospores, as it does in budding. Interestingly, nuclei divided within the suspensor cells, and then one daughter nucleus subsequently migrated into the chlamydospore. Septins were not detected near mitotic nuclei but were localized at chlamydospore necks. At later stages, septins localized throughout the chlamydospore plasma membrane and appeared to form long filamentous structures. Deletion of the CDC10 or CDC11 septins caused greater curvature of cells growing in a filamentous manner and morphological defects in suspensor cells and chlamydospores. These studies identify aspects of chlamydospore morphogenesis that are distinct from bud and hyphal morphogenesis.

Candida albicans↗

PubMed2003

Phosphate availability regulates biosynthesis of two antibiotics, prodigiosin and carbapenem, in Serratia via both quorum-sensing-dependent and -independent pathways.

Serratia sp. ATCC 39006 produces two secondary metabolite antibiotics, 1-carbapen-2-em-3-carboxylic acid (Car) and the red pigment, prodigiosin (Pig). We have previously reported that production of Pig and Car is controlled by N-acyl homoserine lactone (N-AHL) quorum sensing, with synthesis of N-AHLs directed by the LuxI homologue SmaI, and is also regulated by Rap, a member of the SlyA family. We now describe further characterization of the SmaI quorum-sensing system and its connection with other regulatory mechanisms. We show that the genes responsible for biosynthesis of Pig, pigA-O, are transcribed as a single polycistronic message in an N-AHL-dependent manner. The smaR gene, transcribed convergently with smaI and predicted to encode the LuxR homologue partner of SmaI, was shown to possess a negative regulatory function, which is uncommon among the LuxR-type transcriptional regulators. SmaR represses transcription of both the pig and car gene clusters in the absence of N-AHLs. Specifically, we show that SmaIR exerts its effect on car gene expression via transcriptional control of carR, encoding a pheromone-independent LuxR homologue. Transcriptional activation of the pig and car gene clusters also requires a functional Rap protein, but Rap dependency can be bypassed by secondary mutations. Transduction of these suppressor mutations into wild-type backgrounds confers a hyper-Pig phenotype. Multiple mutations cluster in a region upstream of the pigA gene, suggesting this region may represent a repressor target site. Two mutations mapped to genes encoding pstS and pstA homologues, which are parts of a high-affinity phosphate transport system (Pst) in Escherichia coli. Disruption of pstS mimicked phosphate limitation and caused concomitant hyper-production of Pig and Car, which was mediated, in part, through increased transcription of the smaI gene. The Pst and SmaIR systems define distinct, yet overlapping, regulatory circuits which form part of a complex regulatory network controlling the production of secondary metabolites in Serratia ATCC 39006.

4-Butyrolactone↗

PubMed2005

Quorum-sensing-negative (lasR) mutants of Pseudomonas aeruginosa avoid cell lysis and death.

In Pseudomonas aeruginosa, N-acylhomoserine lactone signals regulate the expression of several hundreds of genes, via the transcriptional regulator LasR and, in part, also via the subordinate regulator RhlR. This regulatory network termed quorum sensing contributes to the virulence of P. aeruginosa as a pathogen. The fact that two supposed PAO1 wild-type strains from strain collections were found to be defective for LasR function because of independent point mutations in the lasR gene led to the hypothesis that loss of quorum sensing might confer a selective advantage on P. aeruginosa under certain environmental conditions. A convenient plate assay for LasR function was devised, based on the observation that lasR mutants did not grow on adenosine as the sole carbon source because a key degradative enzyme, nucleoside hydrolase (Nuh), is positively controlled by LasR. The wild-type PAO1 and lasR mutants showed similar growth rates when incubated in nutrient yeast broth at pH 6.8 and 37 degrees C with good aeration. However, after termination of growth during 30 to 54 h of incubation, when the pH rose to > or = 9, the lasR mutants were significantly more resistant to cell lysis and death than was the wild type. As a consequence, the lasR mutant-to-wild-type ratio increased about 10-fold in mixed cultures incubated for 54 h. In a PAO1 culture, five consecutive cycles of 48 h of incubation sufficed to enrich for about 10% of spontaneous mutants with a Nuh(-) phenotype, and five of these mutants, which were functionally complemented by lasR(+), had mutations in lasR. The observation that, in buffered nutrient yeast broth, the wild type and lasR mutants exhibited similar low tendencies to undergo cell lysis and death suggests that alkaline stress may be a critical factor providing a selective survival advantage to lasR mutants.

Adenosine↗

PubMed2005

Prevention of staphylococcal biofilm-associated infections by the quorum sensing inhibitor RIP.

Staphylococcus aureus and Staphylococcus epidermidis associated with implantable medical devices, are often difficult to treat with conventional antimicrobials. Formation of a biofilm and subsequent production of toxins are two distinct mechanisms considered important in foreign body infections. Staphylococcal virulence is caused by a complex regulatory process, which involves cell-to-cell communication through the release and response to chemical signals in a process known as quorum sensing. We explored the possibility of preventing infections by interfering with biofilm formation and toxin production using the quorum sensing inhibitor ribonucleic-acid-III-inhibiting peptide. In our studies ribonucleic-acid-III-inhibiting peptide prevented graft-associated infections caused by all species of staphylococci tested so far, including methicillin resistant S. aureus and S. epidermidis. Ribonucleic-acid-III-inhibiting peptide also enhances the effects of antibiotics and cationic peptides in the clearance of normally recalcitrant biofilm infections. Ribonucleic-acid-III-inhibiting peptide is nontoxic, highly stable, and no resistant strains have been found so far, suggesting that ribonucleic-acid-III-inhibiting peptide may be used to coat medical devices or used systemically to prevent infections. When the target of ribonucleic-acid-III activating protein activity is disrupted, biofilm formation is reduced under flow and static conditions and genes important for toxin production or biofilm formation are down-regulated. These in vitro data help explain why ribonucleic-acid-III-inhibiting peptide seems to be effective in preventing staphylococcal infections.

Animals↗

PubMed2003

Pharmacological inhibition of quorum sensing for the treatment of chronic bacterial infections.

Traditional treatment of infectious diseases is based on compounds that aim to kill or inhibit bacterial growth. A major concern with this approach is the frequently observed development of resistance to antimicrobial compounds. The discovery of bacterial-communication systems (quorum-sensing systems), which orchestrate important temporal events during the infection process, has afforded a novel opportunity to ameliorate bacterial infection by means other than growth inhibition. Compounds able to override bacterial signaling are present in nature. Herein we discuss the known signaling mechanisms and potential antipathogenic drugs that specifically target quorum-sensing systems in a manner unlikely to pose a selective pressure for the development of resistant mutants.

4-Butyrolactone↗

PubMed2003

The virulence activator AphA links quorum sensing to pathogenesis and physiology in Vibrio cholerae by repressing the expression of a penicillin amidase gene on the small chromosome.

Activation of the tcpPH promoter on the Vibrio pathogenicity island by AphA and AphB initiates the Vibrio cholerae virulence cascade and is regulated by quorum sensing through the repressive action of HapR on aphA expression. To further understand how the chromosomally encoded AphA protein activates tcpPH expression, site-directed mutagenesis was used to identify the base pairs critical for AphA binding and transcriptional activation. This analysis revealed a region of partial dyad symmetry, TATGCA-N6-TNCNNA, that is important for both of these activities. Searching the V. cholerae genome for this binding site permitted the identification of a second one upstream of a penicillin V amidase (PVA) gene on the small chromosome. AphA binds to and footprints this site, which overlaps the pva transcriptional start, consistent with its role as a repressor at this promoter. Since aphA expression is under quorum-sensing control, the response regulators LuxO and HapR also influence pva expression. Thus, pva is repressed at low cell density when AphA levels are high, and it is derepressed at high cell density when AphA levels are reduced. Penicillin amidases are thought to function as scavengers for phenylacetylated compounds in the nonparasitic environment. That AphA oppositely regulates the expression of pva from that of virulence, together with the observation that PVA does not play a role in virulence, suggests that these activities are coordinated to serve V. cholerae in different biological niches.

Aminohydrolases↗

PubMed2006

GABA controls the level of quorum-sensing signal in Agrobacterium tumefaciens.

The concentration of GABA increases rapidly in wounded plant tissues, but the implication of this GABA pulse for plant-bacteria interactions is not known. Here we reveal that GABA stimulated the inactivation of the N-(3-oxooctanoyl)homoserine lactone (OC8-HSL) quorum-sensing signal (or "quormone") by the Agrobacterium lactonase AttM. GABA induced the expression of the attKLM operon, which was correlated to a decrease in OC8-HSL concentration in Agrobacterium tumefaciens cultures. The Agrobacterium GABA transporter Bra was required for this GABA-signaling pathway. Furthermore, transgenic tobacco plants with elevated GABA levels were less sensitive to A. tumefaciens C58 infection than were wild-type plants. These findings indicate that plant GABA may modulate quorum sensing in A. tumefaciens, thereby affecting its virulence on plants. Whereas GABA is an essential cell-to-cell signal in eukaryotes, here we provide evidence of GABA acting as a signal between eukaryotes and pathogenic bacteria. The GABA signal represents a potential target for the development of a strategy to control the virulence of bacterial pathogens.

4-Butyrolactone↗

PubMed2004

Deterministic and stochastic modelling of endosome escape by Staphylococcus aureus: "quorum" sensing by a single bacterium.

Deterministic and stochastic models describing quorum sensing by Staphylococcus aureus within an endosome, and the subsequent escape via the production of virulence factors, are developed and analysed. Particular attention is given to a biologically-relevant asymptotic limit of the problem, for which the solutions, including the endosome escape time, can be explicitly characterised in terms of the model parameters.

Computer Simulation↗

PubMed2001

Novel mode of transcription regulation by SdiA, an Escherichia coli homologue of the quorum-sensing regulator.

SdiA, an Escherichia coli homologue of the quorum-sensing regulator, controls the expression of the ftsQAZ operon for cell division. Transcription of ftsQ is under the control of two promoters, upstream ftsQP2 and downstream ftsQP1, which are separated by 125 bp. SdiA activates transcription from ftsQP2 in vivo. Here, we demonstrate that SdiA facilitates the RNA polymerase binding to ftsQP2 and thereby stimulates transcription from P2. Gel shift and DNase I footprinting assays indicated that SdiA binds to the ftsQP2 promoter region between -51 and -25 with respect to the P2 promoter. Activation of ftsQP2 transcription by SdiA was observed with a mutant RNA polymerase containing a C-terminal domain (CTD)-deleted alpha-subunit (alpha 235) but not with RNA polymerase containing sigma(S) or a CTD-deleted sigma(D) (sigma(D)529). In good agreement with the transcription assay, no protection of P2 was observed with the RNA polymerase holoenzymes, E sigma(S) and E sigma(D)529. These observations together indicate that: (i) SdiA supports the RNA polymerase binding to ftsQP2; and (ii) this recruitment of RNA polymerase by SdiA depends on the presence of intact sigmaCTD. This is in contrast to the well-known mechanism of RNA polymerase recruitment by protein-protein contact between class I factors and alpha CTD. In addition to the P2 activation, SdiA inhibited RNA polymerase binding to the ftsQP1 promoter and thereby repressed transcription from P1. Gel shift assays indicate weak binding of SdiA to the P1 promoter region downstream from -13 (or +112 with respect to P2). Neither alpha CTD nor sigma CTD are required for this inhibition. Thus, the transcription repression of P1 by SdiA may result from its competition with the RNA polymerase in binding to this promoter.

Bacterial Proteins↗