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The future of translational synthetic biology hinges on the development of reliable means for connecting smaller functional circuits to realize higher-order networks with predictable behaviours. The LAB bacteriocin systems described here may also be perceived, to some degree, as an example of altruism rather than of selfishness when tolerant or resistant lineages in addition to sensitive target cells are present in the environment of the producer. The habitat is thus expected to create a bottleneck situation as has been discussed for LAB in this review.

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  1. Biometals. Aug;22(4) doi: /s Epub Feb Salmochelin, the long-overlooked catecholate siderophore of Salmonella . Müller SI(1), Valdebenito M, Hantke K. Author information: (1)Lehrstuhl für Mikrobiologie - Organismische Interaktionen, Universität Tübingen, Germany.:
    12 Aug The enterobactin receptor FetA from Neisseria meningitidis [20], the siderophore receptor IroN from Escherichia coli [21], the hemoglobin receptor HgbA from Haemophilus ducreyi [22], surface proteins of the S. aureus Isd heme uptake machinery [23], and a combination of E. coli iron acquisition proteins. (a) The LuxS product DPD spontaneously undergoes cyclization and hydration reactions in solution to form R-THMF (detected by SalmonellaTyphimurium) and S-THMF. . Vibrio harveyi, Bioluminescence, colony morphology, siderophore production, biofilm formation, type III secretion and metalloprotease production, LuxP. 5 Sep As for siderophores, it can be anticipated that the proportion of bacteriocin producers in the population will be positively affected if competition acts on a global scale, i.e. with a high degree of . Staying in the cards game analogy, one could compare LAB bacteriocin production to the game of Casino.
  2. in the Sofitel Reef Casino Cairns. Coat Check/Bag An endophyte nonribosomal peptide synthetase in siderophore biosynthesis is essential for mutualistic interactions Salmonella. The use of by-products in pig production improves the circulation of nutrients in agricultural systems and reduces the environmental load.:
    19 Nov diarioimagen.info Justifiably, Casino Innsbruck is one of the most beautiful Casinos of the world because of its impressive architecture and tasteful decoration surrounded by impressing .. in vitro data show that the increased mobilization of iron can be used by Salmonella for their growth and proliferation. descent dental deaths damaging cuts crawling costumes cone columns Cmpl casino caller bulborbs bolts boast Bandicott Ballou awaken approximately aegis saluting Salts-- saltine salmonella Salivex Salcedo saint's sage's sae saddest saddened sacs sabes S-abilities S'Rabba rundown Rq routing roughness Rosie . 4 1PT8 Crystal structure of the yfdW gene product of E. coli, in complex with oxalate and acetyl-CoA Gruez, A. USA 0 0 0 2WI8 Crystal structure of the triscatecholate siderophore binding protein FeuA from Bacillus subtilis
  3. Fur is a transcriptional and posttranscriptional regulator known to sense iron, suggesting the importance of this mineral to Salmonella within tomatoes. To test whether iron acquisition is essential for Salmonella growth in tomatoes, we tested a ΔfepDGC mutant, which lacks the ability to import iron-associated siderophores .:
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If the dispersion rate is low, it will establish competition on a local scale and thereby promote, for example, spiteful behaviour, as for colicin producers [ 11 , 88 ]. Taking into consideration that the bottleneck habitats of LAB in the environment consist of settings, such as decaying vegetables, with a relatively long duration and a continuous dispersion taking place, it is not unreasonable to assume that the rate of dispersion in such a case instead is high, leading to competition on a global scale.

As for siderophores, it can be anticipated that the proportion of bacteriocin producers in the population will be positively affected if competition acts on a global scale, i. A critical difference to the siderophore system is that the resource the sensitive target cells might mutate into competitors resistant target cells.

The fraction of resources that vanish in this way can also be assumed to depend on the scale of competition being less the more global the social arena is. The importance of scale might however be diminished if more than one type of bacteriocin is produced.

The first multiple bacteriocin-producing LAB described was a strain of Lactococcus lactis that produced several lactococcins [ 92 , 93 ], with a very narrow inhibition spectrum [ 62 ]. Shortly afterwards, multiple bacteriocin production was also discovered in Carnobacterium maltaromaticum [ 56 , 94 , 95 ]. The inhibition spectrum of the carnobacteriocins B1, BM1 and B2 is wider than that of the lactococcins A, B and M see the electronic supplementary material, table S1 and might reflect the type of niche carnobacteria reside in [ 19 ].

Other LAB that produce multiple bacteriocins have subsequently also been found in lactobacilli e. Lactobacillus plantarum [ 96 ] and Lactobacillus sakei [ 97 ] , leuconostocs e. Leuconostoc mesenteroides [ 98 ] and enterococci e. Enterococcus faecium , [ 43 , 99 — ]. The potential synergy effect by producing multiple bacteriocins probably diminishes the possibility for selection of resistant variants.

Such bacteria that could be considered as cheaters include a variety of Gram-positive lineages as well as Gram-negative bacteria, in general. However, Gram-positive tolerant lineages might be selected against if the scale of competition is global as described earlier, whereas Gram-negative bacteria are selected against owing to their increased sensitivity towards organic acids produced by LAB [ , ].

Because the LAB bacteriocin producers are likely to meet ever-changing lineages of target cells in successive bottleneck situations, the model requires that the LAB bacteriocins exhibit relative broad target spectra in order to improve fitness of the producing cells. Indeed, several LAB bacteriocins exhibit such broad spectra towards target species that may be only remotely phylogenetically related, i. Thus, a survey of the literature showed that among selected class I bacteriocins, all 10 showed inhibition against genera other than that to which the producer organism belonged, and this was also the case for 25 out of 30 class II bacteriocins see the electronic supplementary material, table S1.

There is, however, frequently intraspecific variation in bacteriocin susceptibility among target cells [ 97 , — ], which result in the likelihood of the presence of tolerant lineages in mixed culture batch fermentations. The mechanism that confers resistance or tolerance to target cells is, in some instances, owing to differences in the membrane composition [ , , ], but other mechanisms e.

There are indications that resistance phenotypes are associated with fitness costs [ , ]. As mentioned previously, bacteriocin-producing LAB contains an immunity gene s that confers resistance towards own bacteriocin s. In a few cases putative orphan , immunity genes without any clear bacteriocin partner have been reported [ 94 , , ]. The mechanisms for maintaining the presence of such genes in LAB populations will require additional studies, but their occurrence might be explained by the Black Queen hypothesis BQH proposed by Morris et al.

We propose that the lack of fitness cost of bacteriocin production is not of overall importance in an IGP model but this devaluates the usefulness of the rock—paper—scissor model for LAB bacteriocins. Another way to reduce the fitness cost of bacteriocin production is to assess whether the bacteriocin has moonlighting properties [ ], meaning that it serves cellular functions other than interbacterial warfare.

An example is LAB bacteriocins that can also act as signal molecules in a quorum-sensing context [ 23 , 32 , 34 , 35 ]. Also, some bacteriocin-related molecules may exert biological roles unrelated to antagonism [ 31 , 33 , , ]. On the other hand, evidence exists that points towards additional cost of LAB bacteriocin production as LAB loci frequently contain numerous genes involved in bacteriocin production, immunity and secretion [ 19 , 23 — 27 , 34 , 35 , 44 , , ].

However, it should be noted that in the context of bottlenecks in batch fermentations, it is more relevant to study the presence of fitness costs associated with survival. Selfishness, as a social interaction, appears to be promoted by bacteriocin-producing LAB in batch culture habitats that allow for IGP. Contrarily, the production of colicins has been extensively used as a convenient microbial model for the social interaction spite [ 89 , ]. The LAB bacteriocin systems described here may also be perceived, to some degree, as an example of altruism rather than of selfishness when tolerant or resistant lineages in addition to sensitive target cells are present in the environment of the producer.

This combination of potentially two types of social interactions makes LAB bacteriocins an interesting model to explore. This concerns the fact that in many complex microbial communities, the majority of species loose genes necessary for providing leaky common goods when this instead can be provided by a few key species, the black queens.

As bacteriocin producers consume metabolites provided by sensitive strains, at least in theory, the producers may lose genes necessary for metabolizing specific substrates e. In this analogy, IGPrey may, to some extent, resemble black queens with the difference that there most likely are more than just a few such lineages present in a typical LAB batch environment. It would be of interest to examine whether bacteriocin producers may in fact carry fewer genes for metabolizing, for instance, specific carbohydrates than is the case for IGPrey lineages.

Staying in the cards game analogy, one could compare LAB bacteriocin production to the game of Casino. One aim is here to capture as many cards as possible equivalent to nutrients from a layout. However, one can only obtain cards bacteriocin sensitive cells that match the cards of the players' hand bacteriocin producers. Selfishness has, compared with altruism and spite, received little recent attention in microbial models. However, this type of social behaviour is suitable for exploring general ecological interactions such as IGP, which is a very common phenomenon in nature [ 37 , ].

Microbial examples have primarily focused on ciliates acting as predator and intraguild prey, whereas bacteria provided the common resource [ 39 , ]. There are few reports, if any, on IGP including only bacteria, but it has to be kept in mind that the example offered here does not include a genuine IGP mechanism as the general resource for the IGPredator and IGPrey is nutrients from decaying organic material and thus not a prey organism as such. Still, the LAB bacteriocin mechanism offers a model that might be useful for examination of more general aspects of IGP, such as the relationship between IGP and resource competition.

It has been shown theoretically [ ] and experimentally, using ciliates and bacteria [ 39 ], that nutrient-rich environments allows predominance of the IGPredator. This is similar to the population dynamics predicted and observed for colicin producers [ 5 , 7 , 10 , ].

Indeed, the induction of bacteriocins in the late exponential or stationary growth phase by quorum sensing appears to present just such a polymorphism. An example could be the Streptomyces genus, which produces the majority of the natural antibiotics known to man. The genus is primarily found in the soil where it gets nutrition from decaying vegetation [ ]. The habitat is thus expected to create a bottleneck situation as has been discussed for LAB in this review.

Interestingly, like LAB bacteriocin production, antibiotic production in Streptomyces is not initiated before entering the stationary phase, where growth rate slows down and production of aerial mycelium begins [ ].

Both protection against other microbes and recycling of killed sensitive cells have been proposed [ ] as an explanation for this timing of antibiotic production. The induction of antibiotic production upon nutrient exhaustion bottleneck coinciding with the production of aerial mycelium dispersion fits very well into the IGP model presented here and it would be of interest to examine experimentally whether this model could be used to explain Streptomyces antibiotic production.

We have until now only discussed fitness of LAB bacteriocin producers during population bottlenecks in environments where they have experienced a previous logarithmic phase of growth. This system relies on an engineered biological nanofactory comprising an antibody, which functions to bind to the cell surface, and a module of three proteins: Bacterial niches are frequently shared by an amazing variety of bacterial species that often rely on each other to maintain their normal physiological functions.

With this in mind, it seems unlikely that members of a multispecies population would be oblivious to their neighbours. Despite this, the study of interspecies signalling is still in its initial stage: AI-2 remains the best studied interspecies signal to date. Since its discovery, the field has exploded with a myriad of studies into the biology of this molecule in a vast range of species.

Although LuxS is a metabolic enzyme, the disruption of which clearly has effects upon central metabolism, this does not preclude a role in bacterial signalling. After all, incorporating two functions, metabolism and signal synthesis, in one enzyme, could provide a means of coupling the production of AI-2 to the physiological status of the cell.

This signal gives bacteria the potential to assess population numbers, of self and non-self, through integration of different quorum sensing systems, and combine this with information about nutrient availability, growth rate and other environmental cues. Notably, the synthesis of AHL autoinducers and CAI-1 are both associated with the same metabolic pathway as that involved in the synthesis of AI-2, and uptake of this latter molecule is also intrinsically linked, somehow, to metabolic status through the PTS.

Perhaps integrating all these signalling mechanisms provides a global means through which bacteria can coordinate biotic and abiotic information to produce the optimum adaptive capability for the maximum range of situations. This adaptation often involves changes in metabolism, motility, extracellular polysaccharide synthesis, biofilm formation, and similar processes important in virulence.

Targeting such behaviours through the use of chemical analogues or quorum quenching enzymes such as LsrK, which would block or manipulate signalling in mixed species communities, has many important potential applications.

These are not only limited to the treatment of disease but could also enable the manipulation of beneficial behaviours in polyspecies communities such as that of the gut flora. Many questions still surround AI Further research, if carried out thoughtfully, making best use of the available tools to verify whether phenotypes are due to signalling or to metabolism, will shed light on the role of AI-2 in single and polyspecies environments and provide us with better means through which we can understand, exploit or inhibit bacterial behaviours for our own benefit.

We would like to thank the members of the Bacterial Signalling group, Stephen Miller and Rita Ventura for their reading and critical appraisal of this manuscript. Special thanks goes to Stephen Miller for his help with Fig.

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Close mobile search navigation Article navigation. Discovery of a common language: A language for debate: AI-2 in signalling and metabolism. Putting words into action: AImediated signalling in bacteria Catarina S. Abstract Success in nature depends upon an ability to perceive and adapt to the surrounding environment.

View large Download slide. Whole genome expression profiles such as microarrays analysis were not included in this table. DPD supplemented to wild-type strain cultures.

AI-2 quorum sensing affects antibiotic susceptibility in Streptococcus anginosus. Biofilm formation and autoinducer-2 signaling in Streptococcus intermedius: Macromolecular inhibition of quorum sensing: Quorum-sensing autoinducer molecules produced by members of a multispecies biofilm promote horizontal gene transfer to Vibrio cholerae.

LuxS promotes biofilm maturation and persistence of nontypeable haemophilus influenzae in vivo via modulation of lipooligosaccharides on the bacterial surface. Indirect pathogenicity of Haemophilus influenzae and Moraxella catarrhalis in polymicrobial otitis media occurs via interspecies quorum signaling. An efficient synthesis of the precursor of AI-2, the signalling molecule for inter-species quorum sensing. Synthesis of autoinducer 2 by the lyme disease spirochete, Borrelia burgdorferi.

Temporal regulation of enterohemorrhagic Escherichia coli virulence mediated by autoinducer How bacteria talk to each other: Intercellular signalling in Vibrio harveyi: Multiple signalling systems controlling expression of luminescence in Vibrio harveyi: Cross-species induction of luminescence in the quorum-sensing bacterium Vibrio harveyi. The luxS gene is not required for Borrelia burgdorferi tick colonization, transmission to a mammalian host, or induction of disease.

The maltose ATP-binding cassette transporter in the 21st century — towards a structural dynamic perspective on its mode of action. Structure-activity relationship of cinnamaldehyde analogs as inhibitors of AI-2 based quorum sensing and their effect on virulence of Vibrio spp. Structural identification of a bacterial quorum-sensing signal containing boron.

Implication of quorum sensing in Salmonella enterica serovar Typhimurium virulence: LsrR-mediated quorum sensing controls invasiveness of Salmonella typhimurium by regulating SPI-1 and flagella genes. Characterization of monospecies biofilm formation by Helicobacter pylori. A distinctive dual-channel quorum-sensing system operates in Vibrio anguillarum. Chemical synthesis of S -4,5-dihydroxy-2,3-pentanedione, a bacterial signal molecule precursor, and validation of its activity in Salmonella typhimurium.

DNA microarray-based identification of genes controlled by autoinducer 2-stimulated quorum sensing in Escherichia coli. Identification, characterization, and regulation of a cluster of genes involved in carbapenem biosynthesis in Photorhabdus luminescens.

How phosphotransferase system-related protein phosphorylation regulates carbohydrate metabolism in bacteria. The crystal structure of the Escherichia coli autoinducer-2 processing protein LsrF.

Functional analysis of luxS in Staphylococcus aureus reveals a role in metabolism but not quorum sensing. In Helicobacter pylori , LuxS is a key enzyme in cysteine provision through a reverse transsulfuration pathway. Modulation of Pseudomonas aeruginosa gene expression by host microflora through interspecies communication. Crystal structure of Lyme disease variable surface antigen VlsE of Borrelia burgdorferi.

Nucleotide sequence of the regulatory locus controlling expression of bacterial genes for bioluminescence. Autoinducerbased chemical communication in bacteria: Engineered biological nanofactories trigger quorum sensing response in targeted bacteria.

Intra- and interspecies regulation of gene expression by Actinobacillus actinomycetemcomitans LuxS. A genetic analysis of the function of LuxO, a two-component response regulator involved in quorum sensing in Vibrio harveyi. Quorum sensing in bacteria: Cloning and characterization of the Pseudomonas aeruginosa lasR gene, a transcriptional activator of elastase expression. LasR of Pseudomonas aeruginosa is a transcriptional activator of the alkaline protease gene apr and an enhancer of exotoxin A expression.

Altering the communication networks of multispecies microbial systems using a diverse toolbox of AI-2 analogs. Inhibition of Pseudomonas aeruginosa quorum sensing by AI-2 analogs. Autoinducer-2 triggers the oxidative stress response in Mycobacterium avium , leading to biofilm formation. The flagella of enteropathogenic Escherichia coli mediate adherence to epithelial cells. Autoinducer 2 controls biofilm formation in Escherichia coli through a novel motility quorum-sensing regulator MqsR, B Induction of luciferase synthesis in Beneckea harveyi by other marine bacteria.

Regulatory small RNAs circumvent the conventional quorum sensing pathway in pandemic Vibrio cholerae. LuxS and autoinducer 2 in biofilm development. Autoinducer 2 activity in Escherichia coli culture supernatants can be actively reduced despite maintenance of an active synthase, LuxS. Biological nanofactories target and activate epithelial cell surfaces for modulating bacterial quorum sensing and interspecies signaling. Three parallel quorum-sensing systems regulate gene expression in Vibrio harveyi.

Crystal structure of the quorum-sensing protein LuxS reveals a catalytic metal site. Experimental evidence for Moraxella -induced penicillin neutralization in pneumococcal pneumonia. Expression of a luxS gene is not required for Borrelia burgdorferi infection of mice via needle inoculation. The Actinobacillus actinomycetemcomitans ribose binding protein RbsB interacts with cognate and heterologous autoinducer 2 signals. Synthesis and bioluminescence-inducing properties of autoinducer S -4,5-dihydroxypentane-2,3-dione and its enantiomer.

Effects on membrane lateral pressure suggest permeation mechanisms for bacterial quorum signaling molecules. LuxS affects flagellar phase variation independently of quorum sensing in Salmonella enterica serovar typhimurium.

The structure of LsrB from Yersinia pestis complexed with autoinducer Pleiotropic role of quorum-sensing autoinducer 2 in Photorhabdus luminescens. The phosphoenolpyruvate phosphotransferase system: A structural genomics approach to the study of quorum sensing: A stochastic model of Escherichia coli AI-2 quorum signal circuit reveals alternative synthesis pathways.

Crystallization and preliminary X-ray analysis of S-ribosylhomocysteinase from Streptococcus mutans. Regulation of quorum sensing in Vibrio harveyi by LuxO and sigma Quantifying the integration of quorum-sensing signals with single-cell resolution. Revisiting AI-2 quorum sensing inhibitors: Processing the interspecies quorum-sensing signal autoinducer-2 AI Colonization and inflammation deficiencies in Mongolian gerbils infected by Helicobacter pylori chemotaxis mutants.

LuxS-based signaling in Streptococcus gordonii: Synthesis and biological validation of a ubiquitous quorum-sensing molecule. S -ribosylhomocysteine cleavage enzyme from Escherichia coli. Parallel quorum sensing systems converge to regulate virulence in Vibrio cholerae. Salmonella typhimurium recognizes a chemically distinct form of the bacterial quorum-sensing signal AI Vibrio harveyi quorum sensing: Cellular control of the synthesis and activity of the bacterial luminescent system.

Regulation of LuxPQ receptor activity by the quorum-sensing signal autoinducer Ligand-induced asymmetry in histidine sensor kinase complex regulates quorum sensing. Subinhibitory concentrations of cinnamaldehyde interfere with quorum sensing. Mutation of luxS affects motility and infectivity of Helicobacter pylori in gastric mucosa of a Mongolian gerbil model.

Helicobacter pylori uses motility for initial colonization and to attain robust infection. LuxS and expression of virulence factors in Streptococcus intermedius. Sinorhizobium meliloti , a bacterium lacking the autoinducer-2 AI-2 synthase, responds to AI-2 supplied by other bacteria. Phosphoenolpyruvate phosphotransferase system regulates detection and processing of the quorum sensing signal autoinducer LuxS-based quorum sensing does not affect the ability of Salmonella enterica serovar Typhimurium to express the SPI-1 type 3 secretion system, induce membrane ruffles, or invade epithelial cells.

Conjugation factor of Agrobacterium tumefaciens regulates Ti plasmid transfer by autoinduction. A small diffusible signal molecule is responsible for the global control of virulence and exoenzyme production in the plant pathogen Erwinia carotovora.

Biofilm formation and interaction with the surfaces of gallstones by Salmonella spp. The quorum-sensing molecule autoinducer 2 regulates motility and flagellar morphogenesis in Helicobacter pylori.

Helicobacter pylori perceives the quorum-sensing molecule AI-2 as a chemorepellent via the chemoreceptor TlpB. Crystal structure of S-ribosylhomocysteinase LuxS in complex with a catalytic 2-ketone intermediate. Inhibition of biofilm formation and swarming of Escherichia coli by 5Z bromo bromomethylene butyl-2 5H -furanone. Differential gene expression shows natural brominated furanones interfere with the autoinducer-2 bacterial signaling system of Escherichia coli.

Stationary-phase quorum-sensing signals affect autoinducer-2 and gene expression in Escherichia coli. Lack of genomic evidence of AI-2 receptors suggests a non-quorum sensing role for luxS in most bacteria. Developing next generation antimicrobials by intercepting AI-2 mediated quorum sensing.

Stereochemical diversity of AI-2 analogs modulates quorum sensing in Vibrio harveyi and Escherichia coli. Autoinducer-2 influences interactions amongst pioneer colonizing streptococci in oral biofilms. The LuxS family of bacterial autoinducers: Autoinducer 2 is required for biofilm growth of Aggregatibacter Actinobacillus actinomycetemcomitans.

Based on these findings and published results of other investigators on the role of siderophores in intracellular pathogens, a more comprehensive investigation of the importance of siderophores in intracellular infections may be warranted. National Center for Biotechnology Information , U. Journal List Infect Immun v. This article has been cited by other articles in PMC. Abstract One of the nonspecific defense mechanisms of higher animals is their ability to limit iron availability to infecting bacteria.

Bezkorovainy A, Zschocke RH. Structure and function of transferrins. Physical, chemical, and iron-binding properties. The significance of iron in infection. Abolition of the bactericidal function of polymorphs by ferritin-antiferritin complexes.

Isolation and mapping of a uracil-sensitive mutant of Salmonella typhimurium. Hfr formation directed by tn LH-RH in the mesencephalic central grey can potentiate lordosis reflex of female rats. The meningococcus and mechanisms of pathogenicity. Influence of temperature on the biosynthesis of iron transport compounds by Salmonella typhimurium. Plasma iron, copper, and zinc in lizard Dipsosaurus dorsalis: Aromatic-dependent Salmonella typhimurium are non-virulent and effective as live vaccines.

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The tilt change is independent of both the helix length and the presence of tryptophan. In addition, compared to wild-type M2, the H37A mutant displayed lowered sensitivity to proton concentration.

We also found that the solvent accessibility of histidine -containing M2 is greater than without histidine. The comparative results of M2, Vpu and their mutants demonstrated the significance of histidine in a transmembrane helix and the remarkable plasticity of the function and structure of ion channels stemming from changes at a single amino acid site.

Detection and classification of mutagens: A detection and classification system for mutagens has been developed that identifies the six possible base-pair substitution mutations. A set of six Salmonella typhimurium TA to TA strains has been constructed, each of which carries a unique missense mutation in the histidine biosynthetic operon. In addition to the his mutation, these strains carry different auxiliary features that enhance the mutability of the target his mutation.

These include the R factor pKM, which has the SOS-inducible mucAB system; a deletion of the uvrB component of excision repair; and rfa mutations to increase the accessibility of bulky chemicals to the bacteria. Another set of strains TA to TA contain a wild-type rfa gene. The strains have considerably lower spontaneous reversion frequencies and detect a variety of mutagens at a sensitivity comparable to the Salmonella tester strains TA, TA, and TA The low spontaneous frequency of reversion of a mixture of the six tester strains approximately 10 revertants per plate enables a single mutation assay with the mixture that is followed by classification of the type of mutation with the individual strains.

Avian Salmonella infections are important as both a cause of clinical disease in poultry and as a source of food-borne transmission of disease to humans.

Host-adapted salmonellae Salmonella enterica serovar Pullorum and Gallinarum are responsible for severe systemic diseases, whereas numerous sero Mutagenic and genotoxic potential of direct electric current in Escherichia coli and Salmonella thyphimurium strains. Direct electric current has several therapeutic uses such as antibacterial and antiprotozoal action, tissues scarring and regeneration, as well as tumor treatment.

This method has shown promising results in vivo and in vitro, with significant efficacy and almost no side effects. Our results showed these doses did not induce mutagenic or genotoxic effects. Probing the Tautomerism of Histidine. Identification by proton nuclear magnetic resonance of the histidines in cytochrome b5 modified by diethyl pyrocarbonate. Diethyl pyrocarbonate DEP is an electrophilic reagent that is used to modify reversibly the histidine residues of proteins.

Unfortunately, the lability of the acylated histidine adduct usually does not permit the isolation and identification of the modified histidine. By use of MHz proton NMR spectroscopy, it has been possible to identify the C-H resonances of the nonaxial histidines of trypsin-solubilized bovine, rabbit, and porcine cytochrome b5 and therefore observe the interaction of DEP with specific histidine residues of cytochrome b5.

In addition, the pKa of the peripheral histidines of bovine and rabbit cytochrome b5 have been measured in D2O. In the bovine protein it was found that the histidines are modified sequentially with increasing DEP concentration in the order His greater than His greater than His This order is maintained in the rabbit protein with the following additions: His approximately His greater than His greater than or equal to His greater than His The relative reactivity of the peripheral histidines with DEP was rationalized by considering three of their characteristics: Throughout the years, Salmonella nomenclature has suffered continual revisions, due to the confusion created by the different criteria adopted by the several groups of researchers.

At the present time, it is recognized that the genus Salmonella is a single species, composed by seven taxa, with the level of subspecies subsp. The name of four the species type Salmonella is Salmonella enteral sp. The serovar of the taxon I is designated, for instance, Salmonella subsp.

For the other taxa, less frequent in human or animal pathology, the name of the subsp. This criterion has been validated by the International Committee of Systematic Bacteriology and the names of the serovars are included in the Approved Lists of Bacterial Names.

Detection of live Salmonella sp. Salmonella enterica contamination in foods is a significant concern for public health. When DNA detection methods are used for analysis of foods, one of the major concerns is false-positive results from the detection of dead cells. This assay has a detection limit of 40 copies of invA mRNA per reaction. Spinach, tomatoes, jalapeno peppers, and serrano peppers were artificially contaminated with four different Salmonella serovars at levels of 10 5 and less than 10 CFU.

Comparable results were obtained by both methods. Only live Salmonella cells could be detected by this qRT-PCR assay, thus avoiding the dangers of false-positive results from nonviable cells. This assay allows for the fast and accurate detection of viable Salmonella spp. Salmonella infection can cause four predominant clinical syndromes: Salmonella as an aetiological agent in osteomyelitis is essentially rare and salmonella osteomyelitis in itself is predominantly seen in patients with haemoglobinopathies such as sickle cell disease or thalassemia.

There are very few cases reported in the literature in which salmonella osteomyelitis is seen in otherwise healthy individuals. We describe here a case of salmonella osteomyelitis in a young gentleman with no significant comorbidities who presented with fever and severe back pain, having returned from recent foreign travel.

It is therefore important to consider uncommon pathogens in the differential diagnosis of travellers with prolonged fever and insidious symptoms.

Gene inactivation in Lactococcus lactis: Lactococcus lactis strains from dairy and nondairy sources were tested for the ability to grow in the absence of histidine. Among 60 dairy strains tested, 56 required histidine , whereas only 1 of 11 nondairy strains had this requirement. This indicates that adaptation to milk often results in histidine auxotrophy. The histidine operon was detected by Southern hybridization in eight dairy auxotrophic strains tested.

A large part of the histidine operon 8 kb, containing seven histidine biosynthetic genes and three unrelated open reading frames [ORFs] was cloned from an auxotroph, which had an inactive hisD gene, as judged by its inability to grow on histidinol. Complementation analysis of three genes, hisA, hisB, and hisG, in Escherichia coli showed that they also were inactive. Sequence analysis of the cloned histidine region, which revealed In addition, several mutations were detected in the promoter region of the operon.

Northern RNA hybridization analysis showed a much lower amount of the his transcript in the auxotrophic strain than in the prototrophic strain. The mutations detected account for the histidine auxotrophy of the analyzed strain. Cellular transport of L- histidine in Hartnup disease. The urinary excretion, the intestinal absorption, and the elimination of histidine from blood were studied in two patients with Hartnup disease. On standard diet the patients lost a great proportion of the dietary histidine in the urine, whereas the fecal loss was negligible.

A high oral dose of L- histidine gave only a slight increase in plasma histidine and no increase in fecal histidine , but a considerable increase in the urinary histidine output. Intravenously administered L- histidine was eliminated more rapidly than in controls. The lack of increase in plasma histidine after the oral loading may be explained by the rapid elimination from the blood.

This was mainly due to a rapid cellular uptake of histidine which is supposed to be a normal reaction of histidine -deprived cells. Thus the only obvious defect in the histidine transport in Hartnup disease is the reabsorption defect in the renal tubules.

A generally impaired cellular transport of L- histidine is improbable. Structural-dynamical investigation of the ZnuA histidine -rich loop: Comparative homology modelling techniques have been used to model the protein ZnuA from Salmonella enterica serovar Typhimurium using the 3D structure of the homologous protein from Escherichia coli.

Alternative structures of the ZnuA histidine -rich loop, never resolved by the X-ray diffraction method, have been modelled. A model of the apo form, one with the histidine -rich loop deleted and two alternative structures with a second zinc ion bound to the histidine -rich loop, have been generated. In all the modelled proteins, investigated through molecular dynamics simulation, the histidine -rich loop is highly mobile and its fluctuations are correlated to the ligand stability observed in the zinc sites.

Cell fate regulation governed by a repurposed bacterial histidine kinase. One of the simplest organisms to divide asymmetrically is the bacterium Caulobacter crescentus. The DivL pseudo- histidine kinase, positioned at one cell pole, regulates cell-fate by controlling the activation of the global transcription factor CtrA via an interaction with the response regulator RR DivK.

DivL uniquely contains a tyrosine at the histidine phosphorylation site, and can achieve these regulatory functions in vivo without kinase activity. We discovered that DivL's catalytic domains have been repurposed as a phosphospecific RR input sensor, thereby reversing the flow of information observed in conventional histidine kinase HK -RR systems and coupling a complex network of signaling proteins for cell-fate regulation.

Salmonella Infections For Parents. Salmonella Basics Not everyone who ingests Salmonella bacteria will Histidine tag fusion increases expression levels of active recombinant amelogenin in Escherichia coli. Amelogenin is a dental enamel matrix protein involved in formation of dental enamel. In this study, we have expressed two different recombinant murine amelogenins in Escherichia coli: The effects of the histidine tag on expression levels, and on growth properties of the amelogenin expressing cells were studied.

The results of this study showed clearly that both growth properties and amelogenin expression levels were improved for E. The positive effect of the histidine tag on amelogenin expression is proposed to be due to the hydrophilic nature of the histidine tag, generating a more hydrophilic amelogenin, which is more compatible with the host cell.

Human osteoblasts treated with the purified rp H M showed increased levels of secreted osteocalcin, compared to untreated cells. This response was similar to cells treated with enamel matrix derivate, mainly composed by amelogenin, suggesting that the recombinant protein is biologically active.

Thus, the histidine tag favors expression and purification of biologically active recombinant amelogenin. S9 , and methylglyoxal 50 jig, TA, -S9. The usual treatment is antibiotics. Typhoid fever, a more serious disease caused by Salmonella , is L- histidine but not D- histidine attenuates brain edema following cryogenic injury in rats. Oxygen free radicals have been implicated in the genesis of traumatic brain injury and brain edema BE. Recent studies have suggested that hydroxyl radical can initiate lipid peroxidation, thus producing lipid-free radicals that may become important sources of singlet oxygen.

L- histidine , a singlet oxygen scavenger, potentially can be used to treat BE. In this study we investigated the effects of L- histidine and D- histidine on BE following cryogenic injury in rats. Male Wistar rats were anaesthetized with chloral hydrate. Vasogenic BE was produced by a cortical freezing lesion.

Generation of singlet oxygen from photoactivation of rose bengal was studied by electron spin resonance ESR. Animals were separated into four groups: Animals were sacrificed at 24 hours after lesion production and the brain water content was determined by the dry-wet weight method. L- histidine had no effect on rectal and brain temperature.

Election Spin Resonance studies demonstrated that L- histidine is a singlet oxygen scavenger. L- histidine but not D- histidine significantly attenuated BE following cryogenic injury p histidine is useful in the treatment of traumatic BE. Oral L- histidine exerts antihypertensive effects via central histamine H3 receptors and decreases nitric oxide content in the rostral ventrolateral medulla in spontaneously hypertensive rats.

L- histidine is generally found in meat, poultry and fish. To investigate its effects on blood pressure, L- histidine was administered to 9-week-old spontaneously hypertensive rats SHR. Intracerebroventricular injection of L- histidine 0. Chronic treatment with L- histidine inhibited the age-dependent increases in systolic blood pressure and urinary noradrenaline excretion seen in vehicle-treated SHR.

Conversely, intracerebroventricular injection of thioperamide Reverse transcription-polymerase chain reaction analysis revealed that the aortic expression of angiotensin-converting enzyme mRNA was suppressed by chronic treatment with L- histidine. These results suggest that L- histidine decreases blood pressure by attenuating sympathetic output via the central histamine H3 receptor in SHR.

In addition, the antihypertensive effects of L- histidine appear to be associated with an increase in nitric oxide in the RVLM. Histidine provides long-term neuroprotection after cerebral ischemia through promoting astrocyte migration.

The formation of glial scar impedes the neurogenesis and neural functional recovery following cerebral ischemia. Histamine showed neuroprotection at early stage after cerebral ischemia, however, its long-term effect, especially on glial scar formation, hasn't been characterized. With various administration regimens constructed for histidine , a precursor of histamine, we found that histidine treatment at a high dose at early stage and a low dose at late stage demonstrated the most remarkable long-term neuroprotection with decreased infarct volume and improved neurological function.

Notably, this treatment regimen also robustly reduced the glial scar area and facilitated the astrocyte migration towards the infarct core. In wound-healing assay and transwell test, histamine significantly promoted astrocyte migration.

H2 receptor antagonists reversed the promotion of astrocyte migration and the neuroprotection provided by histidine. Therefore, targeting histaminergic system may be an effective therapeutic strategy for long-term cerebral ischemia injury through its actions on astrocytes. Evaluating the mutagenicity of leachates obtained from the bottom ash of a municipal solid waste incinerator by using a Salmonella reverse mutation assay.

The mutagenic potential of leachates derived from the bottom ash of a municipal solid waste incinerator in Taiwan were evaluated using an Ames Salmonella mutagenicity assay with three standard tester strains, TA98, TA, and TA Three types of leachants, leachant A pH 4.

Moreover, two types of bottom ash, nonsieved and sieved bottom ash particle size Ascertaining free histidine from mixtures with histidine -containing proteins using time-resolved photoluminescence spectroscopy. The use of photoluminescent probes for differentiating free amino acids from biomolecules containing the same amino acids is challenging. Photoluminescent probes generally present similar emission spectra when in the presence of either free-amino acids or protein containing those same amino acids.

Probes based on cyclometalated iridium III complexes Ir L 2 sol 2 where L is 2-phenylpyridine, 2- 2,4-difluorophenyl pyridine, or benzo[h]quinolone, and sol is a solvent molecule present long-lived emission when bound to histidine. As a proof-of-concept we demonstrate that free histidine can be discerned from a mixture with histidine -containing proteins by using time-resolved photoluminescence decays.

In the presence of multiple sources of histidine , iridium III probes display a multiexponential decay, which can be fitted by nonlinear least-squares methods to separate the different components.

Because the pre-exponential factor of the ns lifetime is proportional to the concentration of free histidine , we can use it to assess the amount of free histidine in solution even in the presence of proteins such as bovine serum albumin. We also show that iridium III probes displaying different photoluminescence maxima can be produced by modifying the ancillary ligands of the metal complex.

Infections with bacteria of the genus Salmonella are responsible for both acute and chronic poultry diseases. These diseases cause economically significant losses for poultry producers in many nations and absorb large investments of public and private resources in testing and control efforts.

Infections of poultry with bacteria of the genus Salmonella can cause clinical disease, but are of greater current concern as agents of food-borne transmission of illness to humans. However, two nonmotile organisms, S.

Gallinarum, are host-specific for avian species. Distal histidine conformational flexibility in dehaloperoxidase from Amphitrite ornata. The enzyme dehaloperoxidase DHP from the terebellid polychaete Amphitrite ornata is a heme protein which has a globin fold but can function as both a hemoglobin and a peroxidase. As a peroxidase, DHP is capable of converting 2,4,6-trihalophenols to the corresponding 2,6-dihaloquinones in the presence of hydrogen peroxide.

As a hemoglobin, DHP cycles between the oxy and deoxy states as it reversibly binds oxygen for storage. Here, it is reported that the distal histidine , His55, exhibits conformational flexibility in the deoxy form and is consequently observed in two solvent-exposed conformations more than 9. These conformations are analogous to the open conformation of sperm whale myoglobin.

The heme iron in deoxy ferrous DHP is five-coordinate and has an out-of-plane displacement of 0. The observation of five-coordinate heme iron with His55 in a remote solvent-exposed conformation is consistent with the hypothesis that His55 interacts with heme iron ligands through hydrogen bonding in the closed conformation.

Since His55 is also displaced by the binding of 4-iodophenol in an internal pocket, these results provide new insight into the correlation between heme iron ligation, molecular binding in the distal pocket and the conformation of the distal histidine in DHP. Alternative binding modes of l- histidine guided by metal ions for the activation of the antiterminator protein HutP of Bacillus subtilis. Anti-terminator proteins control gene expression by recognizing control signals within cognate transcripts and then preventing transcription termination.

HutP is such a regulatory protein that regulates the expression of the histidine utilization hut operon in Bacillus subtilis by binding to cis-acting regulatory sequences in hut mRNAs.

During the anti-termination process, l- histidine and a divalent ion are required for hutP to bind to the specific sequence within the hut mRNA. This alternative binding mode of the l- histidine ligand to a divalent ion provides further insight into the mechanisms responsible for the activation of RNA binding during the hut anti-termination process. A database of more than histidine biosynthetic genes from different organisms belonging to the three primary domains has been analyzed, including those found in the now completely sequenced genomes of Haemophilus influenzae, Mycoplasma genitalium, Synechocystis sp.

The ubiquity of his genes suggests that it is a highly conserved pathway that was probably already present in the last common ancestor of all extant life. The chromosomal distribution of the his genes shows that the enterobacterial histidine operon structure is not the only possible organization, and that there is a diversity of gene arrays for the his pathway.

Analysis of the available sequences shows that gene fusions like those involved in the origin of the Escherichia coli and Salmonella typhimurium hisIE and hisB gene structures are not universal. In contrast, the elongation event that led to the extant hisA gene from two homologous ancestral modules, as well as the subsequent paralogous duplication that originated hisF, appear to be irreversible and are conserved in all known organisms.

The available evidence supports the hypothesis that histidine biosynthesis was assembled by a gene recruitment process. Prebiotic synthesis of histidyl- histidine. Histidyl- histidine His-His has been synthesized in a yield of up to A trace amount of His trimer was also detected.

Because the imidazole group of His is involved in a number of important enzymatic reactions, and His-His has been shown to catalyze the prebiotic synthesis of glycyl-glycine, we expect this work will stimulate further studies on the catalytic activities of simple His-containing peptides in prebiotic reactions. A modification to the standard continuum electrostatics approach to calculate protein pKas which allows for the decoupling of histidine tautomers within a two state model is presented.

Histidine with four intrinsically coupled protonation states cannot be easily incorporated into a two state formalism because the interaction between the two protonatable sites of the imidazole ring is not purely electrostatic. Effects of histidine and n-acetylcysteine on experimental lesions induced by doxorubicin in sciatic nerve of rats.

In this study, the effect of separate and combined intraperitoneal i. Histidine and n-acetylcysteine were i. Cold and mechanical allodynia were recorded using acetone spray and von Frey filaments tests, respectively. The sciatic nerve damage was evaluated by light microscopy.

Combination treatment with histidine and n-acetylcysteine showed better responses when compared with them used alone. The results of the present study showed peripheral neuroprotective effects for histidine and n-acetylcysteine. Reduction of free radical-induced toxic effects may have a role in neuroprotective properties of histidine and n-acetylcysteine. Cellular transport of l- histidine in Hartnup disease. Effect of dietary electrolytes and histidine on histidine metabolism and acid-base balance in rainbow trout Salmo gairdneri.

Rainbow trout fingerlings were fed diets containing 1. Histidine increased plasma and muscle histidine levels, increased hepatic histidase activity, but did not affect hepatic histidine -pyruvate aminotransferase activity. The electrolyte balance of the diet has a marked effect on the metabolism of histidine in trout. Salmonella typhimurium peptidase active on carnosine.

Wild-type Salmonella typhimurium can use carnosine beta-alanyl-L- histidine as a source of histidine , but carnosine utilization is blocked in particular mutants defective in the constitutive enzyme peptidase D, the product of the pepD gene. Biochemical evidence for assigning carnosinase activity to peptidase D a broad-specificity dipeptidase includes: Genetic evidence indicates that mutations leading to loss of carnosinase activity map at pepD. Several independent pepD mutants have been isolated by different selection procedures, and the patterns of peptide utilization of strains carrying various pepD alleles have been studied.

Many pepD mutations lead to the production of partially active peptidase D enzymes with substrate specificities that differ strikingly from those of the wild-type enzyme. The growth yields of carnosinase-deficient strains growing in Difco nutrient broth indicate that carnosine is the major utilizable source of histidine in this medium. Protonation and geometry of histidine rings. The presence of H atoms connected to either or both of the two N atoms of the imidazole moiety in a histidine residue affects the geometry of the five-membered ring.

Analysis of the imidazole moieties found in histidine residues of atomic resolution protein crystal structures in the Protein Data Bank PDB , and in small-molecule structures retrieved from the Cambridge Structural Database CSD , identified characteristic patterns of bond lengths and angles related to the protonation state of the imidazole moiety.

Using discriminant analysis, two functions could be defined, corresponding to linear combinations of the four most sensitive stereochemical parameters, two bond lengths ND1-CE1 and CE1-NE2 and two endocyclic angles -ND1- and -NE2- , that uniquely identify the protonation states of all imidazole moieties in the CSD and can be used to predict which N atom s of the histidine side chains in protein structures are protonated.

Updated geometrical restraint target values are proposed for differently protonated histidine side chains for use in macromolecular refinement. The antimutagenic activity of Lavandula angustifolia lavender essential oil in the bacterial reverse mutation assay.

Essential oils from Melaleuca alternifolia tea-tree oil and Lavandula angustifolia lavender oil are commonly used to treat minor health problems. Tea-tree oil possesses broad-spectrum antimicrobial activity, and is increasingly used for skin problems. Lavender oil, traditionally used as an antiseptic agent, is now predominantly used as a relaxant, carminative, and sedative in aromatherapy.

Despite their growing use no data are available on their mutagenic potential. In this study, after determining the chemical composition of tea-tree oil and lavender oil, by gas-chromatography and mass spectrometry, we investigated their mutagenic and antimutagenic activities by the bacterial reverse mutation assay in Salmonella typhimurium TA98 and TA strains and in Escherichia coli WP2 uvrA strain, with and without an extrinsic metabolic activation system. Neither essential oil had mutagenic activity on the two tested Salmonella strains or on E.

Conversely, lavender oil exerted strong antimutagenic activity, reducing mutant colonies in the TA98 strain exposed to the direct mutagen 2-nitrofluorene. Its antimutagenic property makes lavender oil a promising candidate for new applications in human healthcare.

Obesity is considered to be accompanied by a chronic low-grade inflammatory state that contributes to the occurrence of many chronic diseases. Our previous study has demonstrated that histidine supplementation significantly ameliorates inflammation and oxidative stress in obese women.

However, the in vivo potential mechanisms are not known. The present study was conducted to investigate the mechanisms underlying the effects of histidine on inflammation in a high-fat diet HFD -induced female obese rat model. An obese model was established in female Sprague-Dawley rats by HFD feeding for 8 weeks and followed by histidine supplementation for another 4 weeks.

Histidine , an essential amino acid for adult dogs. Twenty-seven adult female mongrel dogs were studied to evaluate whether histidine is an essential amino acid. The histidine -free diet was fed to 10 dogs for 5. In the short-term studies, there were no differences between the responses of the dogs fed the histidine -free and histidine -replete diets.

In the long-term studies, dogs fed the histidine -free diet developed a significant decrease in plasma and muscle histidine , muscle carnosine, body weight, hematocrit and serum albumin. The dogs fed the histidine -free diet tried to avoid the feedings, and after several weeks, they often manifested reduced activity and listlessness. One dog died on the 72nd day. None of these manifestations occurred in the dogs fed the histidine -replete diet in the long-term studies.

Plasma zinc and copper were not different in the two groups of dogs. However, at the end of the long-term studies, the dogs fed the histidine -free diet had significantly lower final whole blood zinc and copper concentrations as compared to the histidine -replete dogs.

These findings indicate that histidine is an essential amino acid in adult female dogs. The syndrome associated with histidine -deficiency tends to develop slowly over many days to several weeks. The histidine phosphatase superfamily: The histidine phosphatase superfamily is a large functionally diverse group of proteins. They share a conserved catalytic core centred on a histidine which becomes phosphorylated during the course of the reaction. Although the superfamily is overwhelmingly composed of phosphatases, the earliest known and arguably best-studied member is dPGM cofactor-dependent phosphoglycerate mutase.

The superfamily contains two branches sharing very limited sequence similarity: Human representatives of both branches are of considerable medical interest, and various parasites contain superfamily members whose inhibition might have therapeutic value.

Additionally, several phosphatases, notably the phytases, have current or potential applications in agriculture. The present review aims to draw together what is known about structure and function in the superfamily.

With the benefit of an expanding set of histidine phosphatase superfamily structures, a clearer picture of the conserved elements is obtained, along with, conversely, a view of the sometimes surprising variation in substrate-binding and proton donor residues across the superfamily.

This analysis should contribute to correcting a history of over- and mis-annotation in the superfamily, but also suggests that structural knowledge, from models or experimental structures, in conjunction with experimental assays, will prove vital for the future description of function in the superfamily. Poly-L- histidine downregulates fibrinolysis. The elevated level of histidine -rich glycoprotein was considered a risk factor of inherited thrombophilia.

However, the mode of action remains largely unclear. In the current study, we employ poly-l- histidine PLH mimicking the histidine -rich region and determine whether PLH modulates urokinase uPA -dependent fibrinolysis. In an in vitro model, turbidity appearance and clearance monitored fibrin polymer formation and lysis, respectively.

Fibrin polymer formed upon fibrinogen incubation with thrombin. In the presence of uPA or plasmin, fibrin polymer lysis took place in a dose-dependent manner as a function of time. PLH had no effect on plasminogen activation, as evidenced by no inhibitions on either uPA amidolytic activity or plasmin formation derived from its zymogen.

Nor did PLH show any inhibition on plasmin amidolytic activity. PLH caused a profound delay of plasmin-dependent fibrinolysis upon pre-incubation of either plasmin or fibrinogen with PLH. The observations taken together suggest that the complex [plasmin-PLH-fibrin] formation significantly delayed plasmin-dependent fibrinolysis.

Control of Ligand Binding to Heme Proteins: We have investigated the effect of the distal histidine on the recombination rates of CO and O ,2 to sperm whale myoglobin, separated beta chains of normal human hemoglobin and to the beta chains of hemoglobin Zurich.

The recombination was measured using flash photolysis from to 40 K, on a time scale of ns to s. Lowering the pH of the solution from 7. The distal histidine , His E 7, is identified as the titratable group by observing no pH dependence in the rates when CO binds to the beta chains of hemoglobin Zurich, a mutant of hemoglobin lacking a distal histidine in the beta chains.

We postulate a charge-dipole interaction between the CO and the protonated histidine , since the recombination of the symmetric ligand, O ,2 , is pH independent. The temperature independent energy shift is then used to demonstrate the importance of the final barrier even at K, support the sequential model used and finally to speculate on the structural contributions to the final barrier for binding.

The protein structure is shown to be the major contribution to the final barrier for myoglobin. We then show how the distribution of atomic positions from the X-ray scattering data at 80 K can result in the distribution of activation enthalpies observed between 60 and K. Preliminary studies on the effect of pH on the CO recombination to chloroperoxidase show a reversed effect. The rates increase with increasing pH, unlike myoglobin and beta hemoglobin. However, the pK and energy difference between the protonated and unprotonated states suggest a distal histidine is also being protonated in chloroperoxidase.

Evidence for the presence of essential histidine and cysteine residues in platelet cGMP-inhibited phosphodiesterase. Camp is a major regulator of platelet function. The pH-rate profile plot for this enzyme yields pKa values of 6. It was estimated that 2 mol of histidine residues per mol of enzyme were responsible for the loss of catalytic activity, as deduced from the correlation of the difference spectrum at nm of the DEP-modified cGI-PDE with the enzyme activity.

N-Ethylmaleimide NEM and 5. We conclude that cGI-PDE possesses two essential histidine residues for activity, two additional histidines for cGMP inhibition, and one cysteine residue at the active site.

These data indicate that through the provision of AI-2, H. AI-2 signalling also promotes mutualistic biofilm formation between several species inhabiting the oral cavity.

This same gene in Streptococcus oralis is likewise required for formation of biofilms with Actinomyces naeslundii , a luxS -deficient human commensal. Decreased biofilm formation between luxS mutant S. The mutualistic biofilm established between S. Another species which, despite an inability to produce the molecule, responds to AI-2 produced by neighbouring bacteria is Pseudomonas aeruginosa.

This major pathogen is a member of the oropharyngeal flora OF able to cause mortal pulmonary failure in patients with cystic fibrosis. The expression of a number of important virulence-associated proteins encoded by the genes rhlA rhamnolipid biosynthesis , lasB elastase , exoT exotoxin , phzA1 and phzA2 phenazine synthesis , and fliC flagellar component is upregulated in response to AI These same genes were upregulated when P.

Co-infection with this avirulent microflora also exacerbated the lung injury caused by P. Interestingly, detectable levels of AI-2 were found in sputum samples recovered from cystic fibrosis patients, leading the authors to speculate that interspecies communication between the OF and P. This is one of the few published studies to explore the contribution of interspecies communication to bacterial pathogenicity in the context of the host environment.

More investigation is required to fully establish whether a causal relationship between AI-2 production or signalling by the OF and virulence factor expression and pathogenesis by P. An increasing number of tools with which to investigate AI-2 function at the species and polyspecies level are available; however, in many cases it remains unclear whether phenotypes observed in the absence of LuxS are a consequence of interruption of the AMC, signal disruption, or even a combination of both.

The chemical properties, the potential different sensing mechanisms, integration with other quorum sensing pathways, environmental factors and cellular metabolism all add levels to the challenge of understanding the function of AI Although successful chemical complementation of luxS mutant phenotypes with synthesized AI-2 potentially provides strong evidence that AI-2 is acting as a signal, the innate complexity of this system means that a lack of success does not conclusively prove the opposite.

The studies outlined above highlight that timing of signal production, concentration, requirement for chemical modifications or additional environmental factors, and the percentage of the population responding to the signal can all contribute to the elicitation of productive signalling. These elements are often difficult to identify and appropriately reproduce in vitro , potentially explaining why the addition of AI-2 may have failed to restore behaviours to wild-type levels in some cases.

Supplementation of wild-type bacteria with AI-2 circumvented this problem for A. The physiological relevance of exposing cells to higher concentrations of AI-2 than they themselves produce is debatable; however, this situation could arise naturally in niches containing multiple AIproducing species, arguing the case for the use of this approach.

The possibility that for certain bacteria and growth conditions, any potential AI-2 signalling complementation taking place could be masked by more severe metabolic defects should also be borne in mind. Expression of enzymes that prevent accumulation of intermediates resulting from luxS mutations, exemplified in the use of SahH to restore the methyl cycle in A. The existence of multiple, convergent signalling pathways, as in Vibrio spp. Recently, in many studies showing that deletions in luxS affected metabolism, the possibility that AI-2 is a signal has consequently been discarded.

However, this conclusion is not necessarily appropriate when addition of AI-2 induces metabolic changes unrelated to its synthesis or processing. In light of the recent data associating the function of the Lsr in E. Undoubtedly, identification of AI-2 receptors and the construction of corresponding mutant strains can provide robust evidence that potential AIregulated behaviours are indeed responding to this signal.

On the other hand, in other species, even where AI-2 responses have been observed, the receptors remain a mystery. This type of novel approach, in conjunction with established methods such as genetic screens and the use of bioinformatics, should speed developments in this area, and hopefully provide tools to clarify the role of AI-2 in individual organisms.

The amazing ability of bacteria to evolve and adapt, and their propensity for horizontal gene transfer, has led to the rapid acquisition and spread of multidrug resistance and the re-emergence of infectious diseases as one of the top five causes of human mortality worldwide. From this perspective, AI-2 is of particular economic interest, as a single therapeutic could be developed with broad effects upon a multitude of species or diseases.

Multidisciplinary approaches and techniques are helping to target AIdependent behaviours. The crystallization of receptor-inducer complexes has and will be of great benefit in determining signal structures, important residues for ligand binding, and how such interactions might be disrupted to prevent downstream signalling. In this field, the interference of AIbased signalling, known as quorum quenching, chemical and biological expertise has been brought together in the synthesis of antagonistic analogue molecules with the potential to target any of the steps in the signalling process.

Most approaches have targeted the C1 methyl group of this molecule with linear, branched or cyclic alkyl groups, and even a trifluoromethyl substituent. Given the very different binding sites of the AI-2 receptors of V. Typhimurium, this finding is perhaps not completely surprising.

More recently, DPD analogues with a new stereocenter and a methylene group at C5 targeted due its vicinity to a cavity in both LsrB and LuxP ligand-receptor complexes were also shown to elicit different responses in the two signalling systems tested: Analysis of both receptor structures was used to explain the results.

In LsrB the C5 of the natural ligand is located in an unfilled region suggesting that there would be no significantly different interactions with the protein and the 5 R or 5 S isomers, an observation that was consistent with the results obtained experimentally.

For LuxP the 5 R isomer was a better agonist than the 5 S and visual analysis of the crystal structure indicates that the 5 S methyl is likely to come into steric conflict with the protein. The authors suggested that these results showed that the open-closed equilibrium inherent within the structure of DPD was essential for biological activity. Perhaps a more reasonable hypothesis for the absence of activity of these analogues could result from the loss of the oxygen in the cyclopentane scaffold of the analogues and the coincident loss of hydrogen bonds between the ligand and the residues thought to be essential for ligand binding: Taken together, synthesis and analysis of these DPD analogues provides further insight into AI-2 itself, and the potential for rationally designed therapeutics based on structural analysis of ligand-receptor complexes of new AI-2 quorum sensing modulators.

Alternative means to disrupt quorum sensing have been investigated: Similar strategies have been adopted for interference in AI-2 signalling based on the Lsr system Fig. Addition of purified LsrK to bacterial cultures disrupts the signalling of S. The processing of extracellular AI-2 to P-AI-2 by the kinase adds a negative charge to this molecule, thought to interfere with its receptor binding capabilities.

A nanotechnological approach was used to develop a spatiotemporally controlled manner to deliver AI-2 signal to targeted bacteria. This system relies on an engineered biological nanofactory comprising an antibody, which functions to bind to the cell surface, and a module of three proteins: Bacterial niches are frequently shared by an amazing variety of bacterial species that often rely on each other to maintain their normal physiological functions.

With this in mind, it seems unlikely that members of a multispecies population would be oblivious to their neighbours. Despite this, the study of interspecies signalling is still in its initial stage: AI-2 remains the best studied interspecies signal to date. Since its discovery, the field has exploded with a myriad of studies into the biology of this molecule in a vast range of species.

Although LuxS is a metabolic enzyme, the disruption of which clearly has effects upon central metabolism, this does not preclude a role in bacterial signalling. After all, incorporating two functions, metabolism and signal synthesis, in one enzyme, could provide a means of coupling the production of AI-2 to the physiological status of the cell.

This signal gives bacteria the potential to assess population numbers, of self and non-self, through integration of different quorum sensing systems, and combine this with information about nutrient availability, growth rate and other environmental cues.

Notably, the synthesis of AHL autoinducers and CAI-1 are both associated with the same metabolic pathway as that involved in the synthesis of AI-2, and uptake of this latter molecule is also intrinsically linked, somehow, to metabolic status through the PTS. Perhaps integrating all these signalling mechanisms provides a global means through which bacteria can coordinate biotic and abiotic information to produce the optimum adaptive capability for the maximum range of situations. This adaptation often involves changes in metabolism, motility, extracellular polysaccharide synthesis, biofilm formation, and similar processes important in virulence.

Targeting such behaviours through the use of chemical analogues or quorum quenching enzymes such as LsrK, which would block or manipulate signalling in mixed species communities, has many important potential applications. These are not only limited to the treatment of disease but could also enable the manipulation of beneficial behaviours in polyspecies communities such as that of the gut flora. Many questions still surround AI Further research, if carried out thoughtfully, making best use of the available tools to verify whether phenotypes are due to signalling or to metabolism, will shed light on the role of AI-2 in single and polyspecies environments and provide us with better means through which we can understand, exploit or inhibit bacterial behaviours for our own benefit.

We would like to thank the members of the Bacterial Signalling group, Stephen Miller and Rita Ventura for their reading and critical appraisal of this manuscript. Special thanks goes to Stephen Miller for his help with Fig. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Close mobile search navigation Article navigation.

Discovery of a common language: A language for debate: AI-2 in signalling and metabolism. Putting words into action: AImediated signalling in bacteria Catarina S. Abstract Success in nature depends upon an ability to perceive and adapt to the surrounding environment. View large Download slide. Whole genome expression profiles such as microarrays analysis were not included in this table.

DPD supplemented to wild-type strain cultures. AI-2 quorum sensing affects antibiotic susceptibility in Streptococcus anginosus. Biofilm formation and autoinducer-2 signaling in Streptococcus intermedius: Macromolecular inhibition of quorum sensing: Quorum-sensing autoinducer molecules produced by members of a multispecies biofilm promote horizontal gene transfer to Vibrio cholerae.

LuxS promotes biofilm maturation and persistence of nontypeable haemophilus influenzae in vivo via modulation of lipooligosaccharides on the bacterial surface. Indirect pathogenicity of Haemophilus influenzae and Moraxella catarrhalis in polymicrobial otitis media occurs via interspecies quorum signaling.

An efficient synthesis of the precursor of AI-2, the signalling molecule for inter-species quorum sensing. Synthesis of autoinducer 2 by the lyme disease spirochete, Borrelia burgdorferi. Temporal regulation of enterohemorrhagic Escherichia coli virulence mediated by autoinducer How bacteria talk to each other: Intercellular signalling in Vibrio harveyi: Multiple signalling systems controlling expression of luminescence in Vibrio harveyi: Cross-species induction of luminescence in the quorum-sensing bacterium Vibrio harveyi.

The luxS gene is not required for Borrelia burgdorferi tick colonization, transmission to a mammalian host, or induction of disease. The maltose ATP-binding cassette transporter in the 21st century — towards a structural dynamic perspective on its mode of action. Structure-activity relationship of cinnamaldehyde analogs as inhibitors of AI-2 based quorum sensing and their effect on virulence of Vibrio spp.

Structural identification of a bacterial quorum-sensing signal containing boron. Implication of quorum sensing in Salmonella enterica serovar Typhimurium virulence: LsrR-mediated quorum sensing controls invasiveness of Salmonella typhimurium by regulating SPI-1 and flagella genes. Characterization of monospecies biofilm formation by Helicobacter pylori.

A distinctive dual-channel quorum-sensing system operates in Vibrio anguillarum. Chemical synthesis of S -4,5-dihydroxy-2,3-pentanedione, a bacterial signal molecule precursor, and validation of its activity in Salmonella typhimurium. DNA microarray-based identification of genes controlled by autoinducer 2-stimulated quorum sensing in Escherichia coli. Identification, characterization, and regulation of a cluster of genes involved in carbapenem biosynthesis in Photorhabdus luminescens.

How phosphotransferase system-related protein phosphorylation regulates carbohydrate metabolism in bacteria. The crystal structure of the Escherichia coli autoinducer-2 processing protein LsrF. Functional analysis of luxS in Staphylococcus aureus reveals a role in metabolism but not quorum sensing. In Helicobacter pylori , LuxS is a key enzyme in cysteine provision through a reverse transsulfuration pathway.

Modulation of Pseudomonas aeruginosa gene expression by host microflora through interspecies communication. Crystal structure of Lyme disease variable surface antigen VlsE of Borrelia burgdorferi. Nucleotide sequence of the regulatory locus controlling expression of bacterial genes for bioluminescence.

Autoinducerbased chemical communication in bacteria: Engineered biological nanofactories trigger quorum sensing response in targeted bacteria. Intra- and interspecies regulation of gene expression by Actinobacillus actinomycetemcomitans LuxS. A genetic analysis of the function of LuxO, a two-component response regulator involved in quorum sensing in Vibrio harveyi. Quorum sensing in bacteria: Cloning and characterization of the Pseudomonas aeruginosa lasR gene, a transcriptional activator of elastase expression.

LasR of Pseudomonas aeruginosa is a transcriptional activator of the alkaline protease gene apr and an enhancer of exotoxin A expression. Altering the communication networks of multispecies microbial systems using a diverse toolbox of AI-2 analogs. Inhibition of Pseudomonas aeruginosa quorum sensing by AI-2 analogs. Autoinducer-2 triggers the oxidative stress response in Mycobacterium avium , leading to biofilm formation. The flagella of enteropathogenic Escherichia coli mediate adherence to epithelial cells.

Autoinducer 2 controls biofilm formation in Escherichia coli through a novel motility quorum-sensing regulator MqsR, B Induction of luciferase synthesis in Beneckea harveyi by other marine bacteria. Regulatory small RNAs circumvent the conventional quorum sensing pathway in pandemic Vibrio cholerae.

LuxS and autoinducer 2 in biofilm development. Autoinducer 2 activity in Escherichia coli culture supernatants can be actively reduced despite maintenance of an active synthase, LuxS. Biological nanofactories target and activate epithelial cell surfaces for modulating bacterial quorum sensing and interspecies signaling. Three parallel quorum-sensing systems regulate gene expression in Vibrio harveyi. Here, we will address only the external environment as a LAB habitat, as it provides a striking counterexample compared with the primary habitat facing colicin producers.

The extensive fermentative abilities of LAB indicate that often the natural environment for these bacteria is decaying organic material, which can be viewed as providing the social arena for a batch culture. Thus, the natural habitat of a LAB is characterized by the two very different conditions of feast and famine characteristic for batch cultures summarized in table 1. The selective forces under these two conditions have similarities to the theory of r and K selection, which describes two types of selection, one targeting traits in relation to carrying capacity K and the other traits in relation to the maximal intrinsic rate of natural increase r max [ 64 , 65 ].

Characteristics of the different growth phases for a bacteriocin producer in a batch culture. The bottleneck phase can have a prolonged extension because the period of death is not necessarily a steady decrease but may be interrupted by multiple spurts in multiplication [ 66 ]. Such spurts might reflect periodic selection events and thereby the addition of extra bottlenecks besides the general one provided by the nutrient limitation.

Overall, a strain may survive and dominate the population during a bottleneck in batch fermentations if it has a diminished death rate, similar to what has been argued to be the case for bacterial populations during a transmission phase [ 49 ]. This situation is opposed to the conditions during growth, where a strain may survive and dominate the population if it has an increased growth rate.

Production of broad-spectrum bacteriocins allows, in mixed bacterial communities, at least a partial escape from this scenario. Although many LAB bacteriocins have a bacteriostatic mode of action, they may, however, contribute to an indirect bactericidal effect caused by an induction of autolysis of the sensitive target cell table 2 , a phenomenon that has been used for the acceleration of cheese ripening [ 80 ]. Those nutrients will, for a large part, consist of carbohydrates associated with the cell wall and DNA of the target cell, known to be important for bacterial including LAB survival [ 81 , 82 ] during the stationary growth phase [ 83 ].

Indeed, this role for bacteriocin-producing LAB has been suggested previously as one of the possible functions for Streptococcus mutans bacteriocins [ 31 ]. It is tempting to speculate that the continuous culture systems that constitute the evolutionary context for colicins do not play a similar role for LAB bacteriocins.

Studies examining the effect of selected bacteriocins on the composition of intestinal microbiota, however, gives contradictory results, and this aspect requires further research to reach a conclusion [ 84 , 85 ]. For bacteriocin-producing cells that survive by lysing and eating neighbouring cells, the outcome resembles the cannibalism described for sporulating Bacillus subtilis cells or the fratricide mechanism known from Streptococcus pneumonia [ 86 , 87 ]. However, the broad-spectrum activity observed for many LAB bacteriocins fits better into the social model of IGP, which also offers an alternative to direct competition envisaged for colicins outlined schematically in figure 1.

An important parameter regarding selection for bacteriocin production is the dispersion from one habitat to another, i. By dispersion rate, we here mean the probability for separation of bacteriocin producers and sensitive as well as resistant or tolerant target cells during the transition phase s ; so they end up in new distinct habitats during the next round of batch fermentations. If the dispersion rate is low, it will establish competition on a local scale and thereby promote, for example, spiteful behaviour, as for colicin producers [ 11 , 88 ].

Taking into consideration that the bottleneck habitats of LAB in the environment consist of settings, such as decaying vegetables, with a relatively long duration and a continuous dispersion taking place, it is not unreasonable to assume that the rate of dispersion in such a case instead is high, leading to competition on a global scale.

As for siderophores, it can be anticipated that the proportion of bacteriocin producers in the population will be positively affected if competition acts on a global scale, i. A critical difference to the siderophore system is that the resource the sensitive target cells might mutate into competitors resistant target cells. The fraction of resources that vanish in this way can also be assumed to depend on the scale of competition being less the more global the social arena is.

The importance of scale might however be diminished if more than one type of bacteriocin is produced.

The first multiple bacteriocin-producing LAB described was a strain of Lactococcus lactis that produced several lactococcins [ 92 , 93 ], with a very narrow inhibition spectrum [ 62 ]. Shortly afterwards, multiple bacteriocin production was also discovered in Carnobacterium maltaromaticum [ 56 , 94 , 95 ].

The inhibition spectrum of the carnobacteriocins B1, BM1 and B2 is wider than that of the lactococcins A, B and M see the electronic supplementary material, table S1 and might reflect the type of niche carnobacteria reside in [ 19 ]. Other LAB that produce multiple bacteriocins have subsequently also been found in lactobacilli e. Lactobacillus plantarum [ 96 ] and Lactobacillus sakei [ 97 ] , leuconostocs e. Leuconostoc mesenteroides [ 98 ] and enterococci e. Enterococcus faecium , [ 43 , 99 — ].

The potential synergy effect by producing multiple bacteriocins probably diminishes the possibility for selection of resistant variants. Such bacteria that could be considered as cheaters include a variety of Gram-positive lineages as well as Gram-negative bacteria, in general.

However, Gram-positive tolerant lineages might be selected against if the scale of competition is global as described earlier, whereas Gram-negative bacteria are selected against owing to their increased sensitivity towards organic acids produced by LAB [ , ].

Because the LAB bacteriocin producers are likely to meet ever-changing lineages of target cells in successive bottleneck situations, the model requires that the LAB bacteriocins exhibit relative broad target spectra in order to improve fitness of the producing cells. Indeed, several LAB bacteriocins exhibit such broad spectra towards target species that may be only remotely phylogenetically related, i. Thus, a survey of the literature showed that among selected class I bacteriocins, all 10 showed inhibition against genera other than that to which the producer organism belonged, and this was also the case for 25 out of 30 class II bacteriocins see the electronic supplementary material, table S1.

There is, however, frequently intraspecific variation in bacteriocin susceptibility among target cells [ 97 , — ], which result in the likelihood of the presence of tolerant lineages in mixed culture batch fermentations. The mechanism that confers resistance or tolerance to target cells is, in some instances, owing to differences in the membrane composition [ , , ], but other mechanisms e. There are indications that resistance phenotypes are associated with fitness costs [ , ].

As mentioned previously, bacteriocin-producing LAB contains an immunity gene s that confers resistance towards own bacteriocin s. In a few cases putative orphan , immunity genes without any clear bacteriocin partner have been reported [ 94 , , ]. The mechanisms for maintaining the presence of such genes in LAB populations will require additional studies, but their occurrence might be explained by the Black Queen hypothesis BQH proposed by Morris et al.

We propose that the lack of fitness cost of bacteriocin production is not of overall importance in an IGP model but this devaluates the usefulness of the rock—paper—scissor model for LAB bacteriocins. Another way to reduce the fitness cost of bacteriocin production is to assess whether the bacteriocin has moonlighting properties [ ], meaning that it serves cellular functions other than interbacterial warfare.

An example is LAB bacteriocins that can also act as signal molecules in a quorum-sensing context [ 23 , 32 , 34 , 35 ]. Also, some bacteriocin-related molecules may exert biological roles unrelated to antagonism [ 31 , 33 , , ]. On the other hand, evidence exists that points towards additional cost of LAB bacteriocin production as LAB loci frequently contain numerous genes involved in bacteriocin production, immunity and secretion [ 19 , 23 — 27 , 34 , 35 , 44 , , ].

However, it should be noted that in the context of bottlenecks in batch fermentations, it is more relevant to study the presence of fitness costs associated with survival. Selfishness, as a social interaction, appears to be promoted by bacteriocin-producing LAB in batch culture habitats that allow for IGP. Contrarily, the production of colicins has been extensively used as a convenient microbial model for the social interaction spite [ 89 , ]. The LAB bacteriocin systems described here may also be perceived, to some degree, as an example of altruism rather than of selfishness when tolerant or resistant lineages in addition to sensitive target cells are present in the environment of the producer.

This combination of potentially two types of social interactions makes LAB bacteriocins an interesting model to explore. This concerns the fact that in many complex microbial communities, the majority of species loose genes necessary for providing leaky common goods when this instead can be provided by a few key species, the black queens. As bacteriocin producers consume metabolites provided by sensitive strains, at least in theory, the producers may lose genes necessary for metabolizing specific substrates e.

In this analogy, IGPrey may, to some extent, resemble black queens with the difference that there most likely are more than just a few such lineages present in a typical LAB batch environment.

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This host defense is circumvented through the production of stealth siderophores that are modified in such a way as to prevent siderocalin binding. The importance of nutritional immunity as it pertains to iron is exemplified by the increased susceptibility to infection of individuals with iron overload due to thalassemia and primary hemochromatosis, two of the most common genetic diseases of humans [3].

The impact of this iron overload is perhaps best demonstrated by the enhanced susceptibility of hemochromatosis patients to Vibrio vulnificus infections [4]. Moreover, the administration of excess iron increases the virulence of numerous pathogens in animal models, further highlighting the protection provided by nutritional immunity [2] , [5]. Vertebrates are devoid of free iron, ensuring that all bacterial pathogens encounter a period of iron starvation upon entering their hosts.

In keeping with this, bacterial pathogens have evolved to sense iron depletion as a marker of vertebrate tissue. This sensing typically involves transcriptional control mediated by the iron-dependent repressor known as Fur ferric uptake regulator [6]. Fur binds to target sequences in the promoters of iron-regulated genes and represses their expression in the presence of iron.

In the absence of iron, Fur-mediated repression is lifted and the genes are transcribed. Fur orthologs have been identified in numerous genera from both Gram-negative and Gram-positive bacteria and contribute to the virulence of both animal and plant pathogens [7].

A number of genes encoding for proteins involved in iron utilization have been reported to be positively regulated by Fur during iron-replete conditions [8]. This positive regulation occurs through Fur-mediated repression of a small RNA that represses genes encoding iron utilization proteins. This second level of regulation prevents the use of iron by non-essential enzymes during times of iron starvation. RNA-dependent regulation of iron utilization is a conserved process that has been identified in multiple bacterial pathogens, including Vibrio sp.

The DtxR family was named for its founding member, the diphtheria toxin repressor. In fact, one of the first iron-dependent virulence factors described was diphtheria toxin produced by Corynebacterium diphtheria [2]. DtxR family members negatively regulate genes involved in processes ranging from iron acquisition to virulence factor expression [5]. In addition to sensing alterations in iron levels, bacterial pathogens can also sense heme as a marker of vertebrate tissue.

Heme-responsive activators have been identified in Serratia marcescens , the pathogenic Bordetella , C. Heme-sensing systems presumably alert bacterial pathogens when they are in contact with vertebrate tissues rich in heme, triggering the expression of systems involved in heme-iron acquisition and metabolism. In order to thrive within vertebrates, bacteria must possess mechanisms to evade nutritional immunity.

Perhaps the most elegant mechanism to circumvent iron withholding is employed by Borrelia burgdorferi , the causative agent of Lyme disease. Most pathogens have not evolved this simple defense strategy and instead circumvent iron withholding through high-affinity iron uptake mechanisms that compete against host-mediated sequestration.

These uptake systems can be divided into three main categories: Siderophores are low molecular weight iron-binding complexes that are secreted from bacteria. Siderophores bind iron with an association constant that can exceed 10 50 , enabling bacteria to compete with iron sequestration by transferrin and lactoferrin [2].

Upon removing iron from host proteins, iron-loaded siderophores are bound by cognate receptors expressed at the bacterial surface. The siderophore—iron complex is then internalized into the bacterium and the iron is released for use as a nutrient source.

The importance of siderophores to bacterial virulence is demonstrated by the decreased fitness of siderophore-defective strains in animal models of infection [2] , [7]. Heme acquisition systems typically involve surface receptors that recognize either heme or heme bound to hemoproteins such as hemoglobin or hemopexin. Heme is then removed from hemoproteins and transported through the envelope of bacteria into the cytoplasm. Once inside the cytoplasm, the iron is released from heme through the action of heme oxygenases or reverse ferrochelatase activity [13] — [15].

Bacterial pathogens can also elaborate secreted heme-scavenging molecules that remove heme from host hemoproteins. These molecules, known as hemophores, are functionally analogous to siderophores but are proteins that target heme, whereas siderophores are small molecules that target iron atoms [16]. As is the case with siderophore transport systems, genetic defects in heme acquisition systems reduce bacterial fitness in many animal models of infection [2] , [7]. In addition to acquiring iron from transferrin and lactoferrin through siderophore-based mechanisms, some bacteria are capable of direct recognition of these host proteins.

The most well-studied transferrin and lactoferrin receptors are present in pathogenic members of the Neisseriaceae and Pasteurellaceae [7]. These proteins are modeled to recognize human transferrin or lactoferrin, leading to iron removal and subsequent transport into the bacterial cytoplasm. Human challenge models with Neisseria gonorrhoeae suggest that gonococci expressing both lactoferrin and transferrin receptors exhibit a selective advantage within the host, underscoring the importance of this iron acquisition strategy to these organisms [5] , [17].

A second layer of nutritional immunity employed by vertebrates is to combat siderophore-mediated iron acquisition through the production of siderocalin [18]. Siderocalin, also referred to as lipocalin-2 or neutrophil gelatinase-associated lipocalin NGAL , is a protein that is secreted by neutrophils in response to infection.

Siderocalin binds enterobactin, the primary siderophore of many enteric bacteria, and sequesters the siderophore—iron complex, preventing bacterial uptake.

Mice lacking siderocalin exhibit increased sensitivity to enterobactin-expressing bacteria, demonstrating the pathophysiological relevance of this anti-siderophore defense system [19]. The requirement for iron by bacterial pathogens ensures that iron acquisition systems are expressed and surface exposed during infection. This fact has established surface-exposed iron receptors as viable vaccine candidates for the prevention of bacterial infection.

The enterobactin receptor FetA from Neisseria meningitidis [20] , the siderophore receptor IroN from Escherichia coli [21] , the hemoglobin receptor HgbA from Haemophilus ducreyi [22] , surface proteins of the S.

Resistance to siderocalin is a conserved strategy across multiple pathogenic microbes. A primary bacterial defense against siderocalin involves the production of stealth siderophores.

These molecules represent structurally modified enterobactin-type siderophores that are resistant to siderocalin binding.

The Gram-positive pathogen B. Similarly, Salmonella Typhimurium produces salmochelin, a glycoslyated derivative of enterochelin that is not targeted by siderocalin [26]. The production of stealth siderophores is the most recently uncovered layer in the arms race for nutrient iron during host—pathogen interactions. Undoubtedly, we have not yet discovered the complete armamentarium in this battle that has tremendous implications for the outcome of bacterial infections.

The development of novel tools should help to resolve many of the remaining questions in the field; we highlight how these advances might be exploited in AI-2 quorum quenching, treatment of diseases, and the manipulation of beneficial behaviours caused by polyspecies communities. Bacteria are prevalent throughout the natural world, inhabiting diverse environments from thermal springs to the intensely acidic human stomach. Intrinsic to successful colonization and exploitation of such niches is their ability to sense these surroundings and modify behaviour accordingly.

These modifications are dictated by the interplay between a complex network of signalling pathways: As the natural context for bacterial growth is rarely one of isolation, it is perhaps unsurprising that mechanisms for the detection of and response to other organisms are widespread amongst bacterial species. These mechanisms drive the regulation of phenotypes appropriate to a given social situation, including the induction of many cell density-dependent responses such as the synchronized production and secretion of virulence factors, bioluminescence, biofilm formation and changes in motility.

Such behaviours are typically productive only when enough cells are working in unison, thus it is crucial that expression is limited solely to conditions in which they are beneficial. The term autoinduction was coined to describe the elicitation of phenotypic changes by bacteria in response to self-produced molecules called autoinducers. These molecules accumulate in the extracellular environment until a critical threshold concentration for detection is reached, after which downstream signalling and effector responses ensue.

Characterization of the autoinducer synthase and receptor proteins in V. This means of inducing group behaviours, christened quorum sensing by Fuqua, Winans and Greenberg and illustrated by the V. This creates a positive feedback loop: Many of these molecules are highly specific, produced and recognized by a single species. Through integration with species-specific signalling, this molecule could also enable bacteria to distinguish between self and non-self, providing important information about the local species composition and the potential for behaviour to be fine-tuned to the particular social environment encountered.

In this article, we will provide a historical perspective of the discovery and characterization of AI-2, review the latest developments in signal detection, downstream signalling and responses, and give a critical appraisal of the arguments for and against AI-2 as an interspecies communication molecule.

Given the pressing need for novel therapeutics in the face of rising antibiotic resistance, interference in quorum sensing and the consequent impact on hostile or beneficial bacterial behaviours provides an attractive alternative in the fight against bacterial disease.

The current research strategies adopted and advances made towards the manipulation of AI-2 signalling will also be outlined, highlighting how continued research into the biology and chemistry of AI-2 can help to achieve this goal.

These bacteria were responding to something produced by the neighbouring marine species examined. An AHL-blind reporter strain was constructed which was bioluminescent only upon induction of the AIdependent second system. This strain responded to culture fluids from several unrelated bacterial species. LuxS homologues can now be identified in of the bacterial genomes currently sequenced [based on genomes from the KEGG database http: The AMC and synthesis of autoinducers.

It was later shown that the linear chemical product of LuxS is a very unstable molecule, 4,5-dihydroxy-2,3-pentanedione DPD , providing a likely explanation for why classical chemical and biochemical methods were so unsuccessful in its identification Fig. DPD also spontaneously cyclizes into different isomers in solution, raising the question of which form was detected by AIresponding bacteria Fig.

It was only with the imaginative approach of exploiting the high affinity nature of the V. A further surprise came from the identification of a markedly different enantiomer of DPD, a non-borated R methyl-2,3,3,4-tetrahydroxytetrahydrofuran R -THMF ligand, in the crystal structure of a second AI-2 receptor, LsrB, from Salmonella enterica ssp.

Although the signal synthase, corresponding biosynthetic pathway and chemical products are the same in every AIproducing bacterium tested thus far, these studies demonstrate that the molecule ultimately detected by these bacteria can differ. This was demonstrated experimentally: AI-2 signalling molecules and receptors.

Typhimurium, although the structure of the receptors c , shown by ribbon diagrams coloured in rainbow order from the N- to the C-terminus, reveals much similarity between these two proteins. Inactivation of luxS could result in changes in gene expression as a consequence of defective signalling, methionine metabolism, recycling of homocysteine or accumulation of intermediates of SAM metabolism.

Therefore, to establish whether AI-2 is a bona fide signalling molecule or only a by-product of metabolism in a given species, it is extremely important to discriminate between these metabolic and signalling defects. This receptor is present in this bacteria but the connection to the regulated phenotypes remains to be demonstrated. In many cases, use of such preparations of pure DPD to chemically complement defects in luxS mutant bacteria has successfully demonstrated the role of AI-2 as a quorum sensing molecule.

The Supporting Information, Table S1 details further studies where defects were seen upon disruption of luxS but the link with altered signalling may not have been definitively proven. Even if, in some species, LuxS is only an enzyme of the AMC, the resulting AI-2 could still be used as an information source by other species sharing the same environment, illustrating the complexity of determining how LuxS and AI-2 affect bacterial behaviour at the species and community level.

Beyond the debate regarding the classification of AI-2 as a signal or metabolite, the link between AI-2 production and SAM can have other implications.

In all living organisms, SAM is the main methyl donor in many essential methylation reactions required for cell growth, development and chemotaxis. As shown in Fig. It is perhaps not a coincidence that these three classes of autoinducers all derive from SAM and it is tempting to speculate that the reason for this common connection relates to the benefit of integrating central metabolism with quorum sensing. Since the discovery of luxS , hundreds of studies have been published to further understand AI-2 signalling: Here, while highlighting the progress made regarding AI-2 production, secretion and detection, we will also give emphasis to the open questions awaiting investigation.

The shape and small size of the active site being relatively inaccessible without conformational change suggested the hydrolytic cleavage of a non-peptide molecule. Recently, two different variants of LuxS were found in two naturally occurring strains of Campylobacter jejuni.

As Asp 92 is a conserved amino acid in the LuxS protein of a wide range of bacteria, it is likely that in these organisms this substitution would lead to a loss of AI-2 production. This point mutation could represent a revertible adaptive strategy for gain or loss of function, enabling an advantageous switch between high and low AI-2 production, according to the environmental requirements. Post-translational modification in the form of phosphorylation of Thr 14 of the LuxS from Staphylococcus aureus has been observed; the corresponding increase in enzyme activity was thought to result from indirect changes in the conformation of the active site that stabilize the enzyme—substrate interaction.

Thr 14 residue is conserved across many LuxS homologues; although phosphorylation of this residue could constitute a common mechanism for rapidly modifying LuxS activity across different species, further investigation is required for this supposition to be made firm.

In contrast, in E. Activation by glucose was abolished by supplying cAMP to the culture and a crp deletion mutant clearly showed an increased transcription of luxS when compared to the wild type.

A second sRNA, micA , affects the length and prevalence of luxS transcripts in an RNase III-dependent manner Udekwu, but whether this regulation affects protein amounts, activity, or explains the observed growth dependence of LuxS expression is not yet known. However, because extracellular accumulation of AI-2 in the ydgG mutant, under conditions where uptake of AI-2 is inhibited, is only twofold lower than in the wild type, it is clear that the role of YdgG as an exporter is mild and other mechanisms for AI-2 export must exist.

Thus, it is still unclear how AI-2 exits the bacterial cell in LuxS-containing species. Structures have been determined for members of both the LuxP family, found in Vibrio spp. The AIbinding capability of members of the ribose binding protein RbsB family, i.

Unlike canonical high-affinity substrate-binding proteins, LuxP does not interact with a transport system but modulates the activity of a membrane-spanning sensor protein, LuxQ, upon binding of AI As other two-component regulatory systems, LuxPQ regulates a phosphorylation signal transduction cascade that controls the downstream AI-2 quorum sensing regulon Fig.

LuxP-like receptors have only been found in the Vibrionales, such as V. Vibrio harveyi quorum sensing. Accumulation of phosphorylated LuxO activates the transcription of five regulatory sRNAs, Qrr, which in turn destabilize the luxR mRNA and inhibit expression of this high cell density master regulator. Conversely, Qrr promote expression of AphA, the low cell density regulator, which leads to changes in the regulation of more than genes. Ligand binding promotes the phosphatase activity of these proteins, such that phosphate flow through the pathway is reversed.

The resulting unphosphorylated LuxO does not induce the transcription of Qrr; LuxR is produced which regulates the quorum sensing regulon of V. Note that the V.

The crystal structure of LuxP from V. S -THMF-borate is negatively charged: The relevance of these studies goes well beyond understanding signal transduction in quorum sensing reviewed in Federle, Two-component systems such as the LuxPQ are widely used by bacteria to sense and respond to environmental stimuli.

Hence, structural studies on LuxPQ have served as an excellent model to comprehend, at the molecular level, how bacteria use two-component and phosphorelay systems for environmental adaptation. LsrB is also a high-affinity substrate-binding periplasmic protein.

Crystal structures of LsrB-ligand complexes have been solved for S. Sequence similarity between the three crystallized LsrB-like proteins is striking, with percentage identity between that of S. Typhimurium and that of Y. This study revealed two distinct groups of potential orthologues to the S.

Strikingly, the six residues previously shown to form hydrogen bonds with the AI-2 ligand in the S. These residues were predicted to be essential for ligand binding. Interestingly, all proteins of the second group diverged at residues Asp and Asp , which were shown experimentally to be essential for AI-2 binding, suggesting that these proteins are not functional LsrB receptors. As detection mechanisms must exist in all those bacteria with the ability to respond to AI-2 but have no characterized receptor, in light of the above, it is unlikely that the unidentified sensor proteins involved will be evolutionarily related to LuxP or LsrB.

There is a marked difference between the polarity of the LuxP and LsrB binding sites which is thought to be a major factor in constraining which AI-2 form is bound.

Boron is essential for the AI-2 response in V. As the equilibrium state of AI-2 molecules reflects chemical environmental conditions, it could enable bacteria to detect both their biotic and abiotic context. The different concentration of boron in these two environments could enable V.

The RbsB proteins of both A. Using a combination of luxS , rbsB and lsrB mutant strains of A. This defect was similar to that observed in a luxS mutant, indicating that RbsB might also act as an AI-2 receptor in H. The next step towards a better understanding of the role of RbsB in AI-2 detection will be to determine its structure in complex with the signal, which could reveal whether RbsB binds the same AI-2 isomer as LsrB or an alternative rearrangement.

Structural studies could also reveal the amino acid residues involved in AI-2 binding and open doors through novel bioinformatic studies to identify new RbsB-like AI-2 sensing proteins and clarify whether these proteins constitute a third class of AI-2 receptors. Due to the resulting wealth of literature, this section will focus first on studies describing AI-2 signalling in species containing LuxP- or LsrB-like receptors, then discuss those in which it was clearly demonstrated that AI-2 was acting as a signalling molecule even if the mechanisms of sensing and signal transduction are not yet known.

Several members of the Vibrio genus contain parallel quorum sensing systems: As a result, a synergistic role in the regulation of group behaviours has been attributed to AI-2 signalling, the precise mechanisms and phenotypic effects of which vary from species to species.

Although this synergism makes it difficult to determine the particular contributions of a single autoinducer to the overall response, experiments with mutant V. Signal transduction is most characterized in V. LuxP, which is situated in the periplasm, binds borated-AI-2 and the resulting complex interacts with the cognate membrane histidine kinase, LuxQ. As the concentration of AI-2 changes, the enzymatic activity of this transmembrane protein shifts from kinase to phosphatase.

Both the flux of phosphate through the downstream pathway and the activity of the quorum sensing master regulators, LuxR V. The cytoplasmic phosphotransferase protein, LuxU, is phosphorylated, then transferring the phosphate to a response regulator, LuxO. Conversely, when cell density and autoinducer availability increase, binding of the ligand to its cognate receptor switches LuxQ activity from that of kinase to phosphatase Fig. The flow of phosphate through the pathway is reversed, leaving LuxO in an unphosphorylated state.

The presence of distinct quorum sensing systems with common transduction pathways raises the question as to how and if the different autoinducers can be distinguished by and relate to distinct phenotypic outputs in V. Several studies have shown that various amounts and combinations of the three autoinducers trigger different phenotypic responses. This occurs due to differences in signal strength impact on LuxR protein production and promoter affinity.

Extensive AI-2 quorum sensing regulons exist in these species: One of the paradigms in quorum sensing is that autoinducers accumulate extracellularly with increasing population density. Bacteria with an LsrB-like receptor seem to contradict this paradigm: Current model for AI-2 detection, uptake and signalling via the Lsr system of Escherichia coli. LsrR repression is active and expression of the Lsr system is inhibited. More P-AI-2 is produced and at high cell densities expression of the transporter is further induced.

AI-2 import increases and extracellular levels of AI-2 are rapidly depleted as a result of this positive feedback loop. It was recently proposed that the initial AI-2 uptake occurs via a PTS-dependent transport, but the permeases involved in this process are still unknown. Although homologues of the Lsr transporter have been identified in many bacterial species, including Yersinia spp. A positive feedback loop results, whereby uptake and phosphorylation of AI-2 promote expression of the transporter, which in turn drives more signal uptake and further induction of lsr.

AI-2 is rapidly depleted from the extracellular medium Fig. Thus AI-2 induces its own internalization, phosphorylation and depletion. Recent data from E. This would provide the first pool of AI-2, which is phosphorylated by basal levels of LsrK, relieves lsr repression and initiates Lsr-dependent AI-2 depletion from the extracellular environment Fig.

Importantly, Lsr activation is inhibited in the presence of a constitutive non-phosphorylated form of PTS and thus AI-2 internalization is inherently associated to the phosphorylated levels of PTS. Due to the conserved nature of the PTS, this regulatory mechanism is likely to be conserved in other Lsr-containing bacteria, supported by the repression of Lsr expression in a S.

The physiological function of the Lsr system is not yet clear: It does not appear to be a carbon source, as neither S. As the Lsr system imports self and non-self AI-2, the presence of lsr -containing bacteria, which deplete extracellular AI-2, could also impact upon the behaviours of neighbouring bacteria relying upon this molecule for signalling proposes. AIdependent quorum sensing has been implicated in the induction of several important behaviours in E.

Addition of AI-2 to wild-type E. AI-2 also appears to act as a chemoattractant for E. As chemotaxis towards AI-2 was unaffected in the absence of LsrC, uptake of the molecule is seemingly dispensable for this process. Concentration-dependent chemoattraction of enterohaemorrhagic E. Similarly, luxS mutant enteropathogenic E. Overall, these studies show that in E. This indicates that regulatory elements in the promoter region of luxS are important for biofilm formation, and that concentration and timing of AI-2 production and therefore complementation with AI-2 are likely to be crucial for correct induction of signalling.

This may partly explain the existence of contradictory studies regarding the role of AI-2 but does not account for the discrepancy between certain reports of S. As a result, the possibility that the Lsr system might potentiate interference in the AIregulated behaviours of neighbouring, non-self bacteria remains a reasonable hypothesis.

LuxS and AIdependent phenotypes have also been studied in other bacteria possessing Lsr-like receptors, Photorhabdus luminescens , for example. This organism has two distinct life cycle phases: Comparison of the expression profiles of wild-type and luxS mutant bacteria grown in the presence of enzymatically synthesized AI-2 showed that this molecule regulates more than genes in P. Amongst them are genes encoding outer membrane-associated proteins such as flagella and pili, those involved in virulence, and those that promote resistance to oxidative stress.

Deletion of luxS in A. Defects in biofilm formation were rescued by addition of partially purified AI-2 to luxS mutant strains, whereas expression of the enzyme SahH which presumably bypasses the metabolic need of LuxS; Fig.

These results strongly suggest that LuxS function in this organism is signal-based rather than metabolic, strengthened by the observation that deletions in lsrB or the second AI-2 receptor gene of A. Simultaneous inactivation of both receptors reduces biofilm formation to that seen in a luxS mutant strain. In summary, these two receptors contribute additively to the elicitation of AIdependent responses necessary for biofilm assembly in A. AI-2 and luxS -dependent changes in bacterial behaviour, including those directly or indirectly associated with virulence, have been demonstrated for several species of Gram-negative bacteria in which the signal transduction machinery remains unknown.

For example, in H. This molecule is also a chemorepellant for H. Importantly, motility, chemotaxis and LuxS are all required by H. However, a direct link between AIdependent motility and virulence in vivo is yet to be shown. The role of LuxS in B. This organism does not have a full AMC as it does not have the enzymes to convert homocysteine the other product of the LuxS enzyme into methionine Fig. Addition of AI-2 to wild-type cultures of B.

Despite this potential link between AI-2 and virulence, luxS is dispensable for the natural colonization of tick vectors by B. Deletion of luxS in Actinobacillus pleuropneumoniae , the causative agent of porcine pleuropneumonia, impairs its capabilities for biofilm formation, cell adherence, growth in iron-restricted conditions, and virulence in mice.

It is, however, difficult to distinguish whether LuxS is functioning predominantly in signalling or metabolism in this species: These apparent inconsistencies can be attributed to the fact that, again, finely regulated levels of AI-2 are likely required for proper function of the system, which are simply not provided upon co-culture with wild-type bacteria.

Despite the relative paucity of knowledge surrounding AI-2 detection and signal transduction in Gram-positive bacteria, responses by such organisms to the presence or absence of this molecule have been described. Differing reports exist as to the function of AI-2 in S.

Doherty and colleagues propose that the predominant role for LuxS in this species is metabolic, not signalling, for two reasons: Additionally, it was observed that in S. Given that the cap system is upregulated during invasive S.

AI-2 regulates the transcription of many genes, including those encoding acetoin dehydrogenase, gluconokinase, LrgB, nitrite extrusion protein and a fructose PTS subunit in a second Staphylococcal species, Staphylococcus epidermidis. In many studies, monospecies experimental set-ups have been used to determine whether LuxS- and AIdependent signalling regulate bacterial behaviour. Although these simplified systems are less variable and facilitate the analysis of individual players, bacteria rarely exist in such isolated contexts in nature.

It may only be in polyspecies communities that the right context for proper induction of AI-2 signalling, and observation of the downstream effects or their benefits, is provided. One of the first studies to address this issue made use of simple co-culture systems to demonstrate that AI-2 produced by one species can influence gene expression in others: This proof of principle was given greater strength by the observation that E. As haemagglutinin protease facilitates V. Similar approaches analysing the interplay between two species from a particular niche have subsequently been adopted to investigate interspecies signalling in medically relevant polymicrobial communities such as the nasopharygeal flora.

Interestingly, increased loads of M. These data indicate that through the provision of AI-2, H. AI-2 signalling also promotes mutualistic biofilm formation between several species inhabiting the oral cavity.

This same gene in Streptococcus oralis is likewise required for formation of biofilms with Actinomyces naeslundii , a luxS -deficient human commensal. Decreased biofilm formation between luxS mutant S. The mutualistic biofilm established between S. Another species which, despite an inability to produce the molecule, responds to AI-2 produced by neighbouring bacteria is Pseudomonas aeruginosa.

This major pathogen is a member of the oropharyngeal flora OF able to cause mortal pulmonary failure in patients with cystic fibrosis.

The expression of a number of important virulence-associated proteins encoded by the genes rhlA rhamnolipid biosynthesis , lasB elastase , exoT exotoxin , phzA1 and phzA2 phenazine synthesis , and fliC flagellar component is upregulated in response to AI These same genes were upregulated when P.

Co-infection with this avirulent microflora also exacerbated the lung injury caused by P. Interestingly, detectable levels of AI-2 were found in sputum samples recovered from cystic fibrosis patients, leading the authors to speculate that interspecies communication between the OF and P. This is one of the few published studies to explore the contribution of interspecies communication to bacterial pathogenicity in the context of the host environment.

More investigation is required to fully establish whether a causal relationship between AI-2 production or signalling by the OF and virulence factor expression and pathogenesis by P. An increasing number of tools with which to investigate AI-2 function at the species and polyspecies level are available; however, in many cases it remains unclear whether phenotypes observed in the absence of LuxS are a consequence of interruption of the AMC, signal disruption, or even a combination of both.

The chemical properties, the potential different sensing mechanisms, integration with other quorum sensing pathways, environmental factors and cellular metabolism all add levels to the challenge of understanding the function of AI Although successful chemical complementation of luxS mutant phenotypes with synthesized AI-2 potentially provides strong evidence that AI-2 is acting as a signal, the innate complexity of this system means that a lack of success does not conclusively prove the opposite.

The studies outlined above highlight that timing of signal production, concentration, requirement for chemical modifications or additional environmental factors, and the percentage of the population responding to the signal can all contribute to the elicitation of productive signalling. These elements are often difficult to identify and appropriately reproduce in vitro , potentially explaining why the addition of AI-2 may have failed to restore behaviours to wild-type levels in some cases.

Supplementation of wild-type bacteria with AI-2 circumvented this problem for A. The physiological relevance of exposing cells to higher concentrations of AI-2 than they themselves produce is debatable; however, this situation could arise naturally in niches containing multiple AIproducing species, arguing the case for the use of this approach.

The possibility that for certain bacteria and growth conditions, any potential AI-2 signalling complementation taking place could be masked by more severe metabolic defects should also be borne in mind. Expression of enzymes that prevent accumulation of intermediates resulting from luxS mutations, exemplified in the use of SahH to restore the methyl cycle in A.

The existence of multiple, convergent signalling pathways, as in Vibrio spp. Recently, in many studies showing that deletions in luxS affected metabolism, the possibility that AI-2 is a signal has consequently been discarded. However, this conclusion is not necessarily appropriate when addition of AI-2 induces metabolic changes unrelated to its synthesis or processing. In light of the recent data associating the function of the Lsr in E.

Undoubtedly, identification of AI-2 receptors and the construction of corresponding mutant strains can provide robust evidence that potential AIregulated behaviours are indeed responding to this signal.

On the other hand, in other species, even where AI-2 responses have been observed, the receptors remain a mystery. This type of novel approach, in conjunction with established methods such as genetic screens and the use of bioinformatics, should speed developments in this area, and hopefully provide tools to clarify the role of AI-2 in individual organisms.

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