Journal of Laboratory Physicians
Home About us Ahead of print Current issue Back issues Subscribe Instructions Contact Login 
Wide layoutNarrow layoutPrint this page  Email this page Bookmark this page Small font size Default font size Increase font size 

   Table of Contents     
Year : 2011  |  Volume : 3  |  Issue : 1  |  Page : 4-11  

Quorum sensing and bacterial pathogenicity: From molecules to disease

1 Department of Microbiology, Pt. B.D. Sharma, PGIMS, Rohtak - 124 001, India
2 Department of Microbiology, GMCH, Sector-32, Chandigarh, India

Date of Web Publication2-Apr-2011

Correspondence Address:
Antariksh Deep
Department of Microbiology, Pt. B.D. Sharma, PGIMS, Rohtak - 124 001
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0974-2727.78553

Rights and Permissions

Quorum sensing in prokaryotic biology refers to the ability of a bacterium to sense information from other cells in the population when they reach a critical concentration (i.e. a Quorum) and communicate with them. The "language" used for this intercellular communication is based on small, self-generated signal molecules called as autoinducers. Quorum sensing is thought to afford pathogenic bacteria a mechanism to minimize host immune responses by delaying the production of tissue-damaging virulence factors until sufficient bacteria have amassed and are prepared to overwhelm host defense mechanisms and establish infection. Quorum sensing systems are studied in a large number of gram-negative bacterial species belonging to α, β, and γ subclasses of proteobacteria. Among the pathogenic bacteria, Pseudomonas aeruginosa is perhaps the best understood in terms of the virulence factors regulated and the role the Quorum sensing plays in pathogenicity. Presently, Quorum sensing is considered as a potential novel target for antimicrobial therapy to control multi/all drug-resistant infections. This paper reviews Quorum sensing in gram positive and gram negative bacteria and its role in biofilm formation.

Keywords: Autoinducer, acyl homoserine lactone, biofilm, Quorum sensing

How to cite this article:
Deep A, Chaudhary U, Gupta V. Quorum sensing and bacterial pathogenicity: From molecules to disease. J Lab Physicians 2011;3:4-11

How to cite this URL:
Deep A, Chaudhary U, Gupta V. Quorum sensing and bacterial pathogenicity: From molecules to disease. J Lab Physicians [serial online] 2011 [cited 2019 Dec 9];3:4-11. Available from:

   Introduction Top

Quorum sensing in prokaryotic biology refers to the ability of a bacterium to sense information from other cells in the population when they reach a critical concentration (i.e. a Quorum). The phenomenon of Quorum sensing, or cell-to-cell communication, relies on the principle that when a single bacterium releases autoinducers (AIs) into the environment, their concentration is too low to be detected. However, when sufficient bacteria are present, AI concentrations reach a threshold level that allows the bacteria to sense a critical cell mass and, in response, to activate or repress target genes. [1]

The discovery of intercellular communication among bacteria has led to the realization that bacteria are capable of coordinated activity that was once believed to be restricted to multicellular organisms. The capacity to behave collectively as a group has obvious advantages, for example the ability to migrate to a more suitable environment/better nutrient supply and to adapt new modes of growth, such as sporulation or biofilm formation, which may afford protection from deleterious agents. The "language" used for this intercellular communication is based on small, self-generated signal molecules called as autoinducers (AIs). Through the use of AIs, bacteria can regulate their behavior according to population density. [2]

It is now known that a significant portion of bacterial genome (4-10%) and proteome (≥20%) can be influenced by Quorum sensing. This only implies that Quorum sensing is a mechanism used by pathogenic bacteria not only to modulate virulence factor production but also to adapt to the metabolic demands of living in community. [3],[4],[5],[6],[7]

Quorum sensing is a generic regulatory mechanism used by many Gram negative bacteria and Gram positive bacteria to perceive and respond to factors as varied as changing microbial population density and the expression of specific genes. The concentration of a signal molecule reflects the density of bacterial cells in a defined environment, and the perception of a threshold level of that signal indicates that the population is "quorate" that is sufficiently dense to make a behavioral group-based decision. Quorum sensing is thought to afford pathogenic bacteria a mechanism to minimize host immune responses by delaying the production of tissue-damaging virulence factors until sufficient bacteria have amassed and are prepared to overwhelm host defense mechanisms and establish infection. [8]

   Historical Aspects Top

Bacteria were for a long time believed to exist as individual cells that sought primarily to find nutrients and multiply. More than 30 years ago microbiologists found a way to induce luminescent bacteria to emit light prematurely. By adding cell-free culture fluid from a bright bioluminescent culture at high cell density to a non-luminous low cell density culture, they were able to eliminate the characteristic lag in the bioluminescence. [8],[9],[10] Nealson et al, proved that the "light switch" that controls the bioluminescence genes in the marine bacterium Vibrio (formerly Photobacterium) fischeri was cell density dependent, and they hypothesized that this light switch was controlled by AI signal produced by bacteria. [10]

In the above-mentioned example of bioluminescence, it was noted that bioluminescence could occur only after the AI accumulated in cultures to a threshold level that was attained at high cell density (>10 7 CFU/ml). [11] Eberhard et al, went on to elucidate the structure of the AI molecule that was responsible for this effect, the first known acyl-homoserine lactone (AHL), 3-oxo-hexanoyl-homoserine lactone (3-oxo-C6-HSL). [12] 3-oxo-C6-HSL was found to freely diffuse from bacterial cells into the surrounding medium and vice-versa. This phenomenon of cell density dependent auto induction of specific bacterial genes involves two conserved regulatory gene products: (i) a Lux I-type acyl-HSL synthase and (ii) a Lux R-type transcriptional activator whose activity requires a particular acyl-HSL made by the cognate Lux I enzyme. [13] In addition to the Lux R/Lux I control, a second Quorum sensing system regulates the luminescence (lux) genes in V. fischeri. This second system consists of an acyl-HSL synthase, AinS, which directs the synthesis of octanoyl-HSL (C8-HSL). V. fischeri ainS mutants exhibited early luminescence, whereas the addition of C8-HSL delayed luminescence in cultures of wild type cells. [14] These examples illustrate how timing of a Quorum-sensing-controlled (QSC) process can be advanced merely by early exposure of the cells to a critical concentration of acyl-HSL. QSC phenomenon includes antibiotic production, virulence gene expression and other processes in many diverse bacteria.

Quorum sensing in Gram negative bacteria

AHL-mediated Quorum sensing systems are studied in a large number of Gram negative bacterial species belonging to the α, β, and γ subclasses of proteobacteria, including bacteria in the genera Agrobacterium, Aeromonas, Burkholderia, Chromobacterium, Citrobacter, Enterobacter, Erwinia, Hafnia, Nitrosomonas, Obesumbacterium, Pantoea, Pseudomonas, Rahnella, Ralstonia, Rhodobacter, Rhizobium, Serratia, Vibrio, Xenorhabdus, and  Yersinia More Details. Among the Gram negative bacteria, the most well-studied Quorum sensing system is the LuxR-LuxI homologous system and the cognate signal molecules: N-acyl-homoserine lactones (AHLs); similar to the system first studied in the marine bacteria Vibrio fischeri. [9]

The vast majority of gram negative Quorum sensing systems that have been studied thus far utilize N- AHLs as signaling molecules. When in high enough concentrations, these molecules can bind to and activate a transcriptional activator, or R protein, which in turn induces expression of target genes. The use of biosensors to screen spent culture supernatants has led to the discovery that AHLs are produced by a plethora of unrelated bacteria. Biosensors typically consist of a QSC promoter fused to a reporter such as lac Z or the lux operon. These biosensor strains contain a functional R protein but lack the AHL synthase enzyme; therefore, promoter activity depends on the presence of exogenous AHL. Despite the fact that R protein are exquisitely sensitive to their cognate AHLs, some infidelity does exist and this infidelity enables R proteins to be responsive to a range of AHL molecules, albeit higher concentrations of non-cognate AHL are usually required for activation. [2]

It is becoming apparent that in addition to AHLs, alternative gram negative signaling molecules do exist. For example, the plant pathogen Ralstonia solanacearum produces 3-hydroxy-palmitic acid methyl ester as a novel signaling molecule, which together with AHLs is used to regulate virulence. [15] Xanthomonas campestris, a cabbage pathogen, produces a diffusible extra cellular factor, which has yet to be chemically characterized but is not an AHL. [16] In Pseudomonas aeruginosa, a third AI, designated PQS (Pseudomonas Quinolone Signal), was identified that is different from the other two AHL AIs produced by this organism, in that it is a 2-heptyl-3hydroxy-4-quinolone. [3],[17],[18],[19] The structural similarity between PQS and antimicrobial quinolones is quite intriguing, although preliminary studies have showed no antimicrobial activity associated with PQS. [17] Butyrolactones have been isolated from Pseudomonas aureofaciens culture supernatants, and recently a novel family of signaling compounds, identified as diketopiperazines (DKP), were discovered in cell-free supernatants of P. aeruginosa, P. fluorescens, P. alcaligenes, Enterobacter agglomerans and Citrobacter freundii. [20]

Quorum sensing in Pseudomonas aeruginosa

With regard to bacteria that utilize Quorum sensing as part of their pathogenic life style, P. aeruginosa is perhaps the best understood in terms of the virulence factors regulated and the role the Quorum sensing plays in pathogenicity. Classified as an opportunistic pathogen, P. aeruginosa primarily infects individuals who are immunocompromised, such as patients with cancer or AIDS or those having breaches in normal barriers caused by burns, indwelling medical devices, or prolonged use of broad-spectrum antibiotics. [21],[22],[23],[24] P. aeruginosa has an impressive armament of both cell-associated and extra cellular virulence factors. Expression of many of the extracellular factors is not constitutive but rather cell-density dependent with maximum protease production occurring during the late logarithmic and early stationary phases of growth. Two intertwined Quorum sensing systems have been shown to be involved in virulence, biofilm development, and many other processes in P. aeruginosa. The first system (Las) was discovered by Iglewski and colleagues and consists of a lasI -encoded acyl-HSL synthase and the lasR-encoded transcriptional activator. [25],[26] The second system (Rhl) was found by a number of investigators and consists of an rhl I-encoded acyl-HSL synthase and an rhlR-encoded transcriptional activator. [27],[28],[29],[30] In the respective Quorum sensing systems each produce and respond to a specific acyl-HSL; LasI directs the synthesis of 3-oxo-dodecanoyl-HSL (3-oxo-C12-HSL) and RhlI directs the synthesis of butyryl -HSL (C4-HSL). [31]

Recently, Whiteley et al, using a P. aeruginosa las I and rhlI double mutant identified nearly 40 qsc genes that showed a five-fold or greater response to exogenously added acyl-HSL signals. The qsc genes were classified based on the temporal pattern of their responses to cells grown in presence of Las signal, 3-oxo-C12-HSL and/or the Rhl signal, CH-HSL. A number of "early" qsc genes were found that responded immediately to exogenously added signals, suggesting that these genes behave like the lux genes of V. fischeri and the carbapenem biosynthesis genes of Erwinia. Since these seminal observations were made, a number of other proteins have been found that support this hypothesis, including the stationary phase sigma factor RpoS, a third LuxR homolog (qscR), a secondary metabolite regulator, RsmA and the stringent response protein Rel A, all of which are involved in modulating expression of genes. qscR was found to negatively regulate expression of both rhlI and the 3-oxo-C12-HSL synthase gene, LasI. P. aeruginosa qscR mutants showed early activation of a number of qsc genes and premature synthesis of both signals, C4-HSL and 3-oxo-C12-HSL. [25],[32],[33],[34],[35],[36] Over expression of the rsmA gene product resulted in decreased production of qsc virulence factors and acyl-HSLs whereas deletion of rsmA led to early activation of lasI and thus early synthesis of 3-oxo-C12-HSL. [35] RsmA, RpoS, QocR all negatively regulate the Rhl or Las Quorum sensing systems, thus preventing early activation of these systems.

Quorum sensing in P. aeruginosa is involved in regulating expression of a number of virulence factors, and as such, this regulation is believed to play an important role in the pathogenicity of this organism. Using a number of different animal models, this presumption has been confirmed. In the neonatal mouse model of pneumonia, a lasR deficient strain of P. aeruginosa was found to have significantly decreased virulence compared to that of parent. [37] Analysis of lasI mutant, a rhlI mutant and a lasI, rhlI double mutant in the same model revealed markedly decreased virulence, with the most notable reduction seen in double I mutant. [38] In a burned mouse model, strains deficient in lasR, lasI, rhlI or both lasI and rhlI were found to be less virulent in vivo than in the parental strain. In addition, the total number of bacteria recovered from the spleens, livers, and skin of mice infected with the different mutants were significantly lower than those for the parental strain. These findings indicate that Quorum sensing plays an important role in the dissemination of P. aeruginosa throughout the body of burned mouse. In a study employing three different models of infection, namely Caenorhabditis elegans (nematode), Arabidopsis thaliana (plant) and a burned mouse model, a lasR-deficient mutant generated through random mutagenesis exhibited greatly reduced virulence in all these models. These studies are extremely exciting because they suggest that the three aforementioned genes, which are all linked to Quorum sensing, contribute to trans-kingdom virulence of P. aeruginosa. Moreover, using the less costly and simpler plant or nematode model of infection enables identification of genes required for infection of other species. In the future, it will be intriguing to see if other bacteria that infect multiple species and employ Quorum sensing as part of their pathogenic lifestyles have genes that contribute to virulence in such diverse hosts. [39],[40]

Quorum sensing in Enterohemorrhagic  Escherichia More Details coli O157:H7

The infection by Enterohemorrhagic Escherichia coli (EHEC) O157:H7 can lead to potentially severe gastroenteritis and other extraintestinal manifestations, including fever, meningitis, and septicemia. The EHEC also express Shiga toxin (Stx) in the intestine which also has its receptors located in the kidneys and the CNS. Stx is a potent inhibitor of protein synthesis and can get absorbed systemically leading to hemolytic uremic syndrome (HUS), seizures, cerebral edema and coma. More so, in the management of EHEC infections, antimicrobial agents and antimotility agents are contraindicated as they promote the expression and release of Stx, thereby increasing the occurrence and severity of HUS and CNS involvement. For all these reasons, it becomes more imperative, the need for innovative and cost-effective treatment modalities. [41],[42],[43]

EHEC senses three signals to activate transcription of virulence genes: a bacterial aromatic AI (AI-3), produced by normal GI flora and two hormones (epinephrine/norepinephrine), produced by the host. Any of these signal molecules can trigger the QseC membrane bound sensor activity, ultimately leading to transcription of virulence genes. The QseC also activates the expression of second sensor QseE which also helps in fine tuning the signaling cascade. All these transcription events lead to formation of attachment and effacing lesions in the intestine and the production of Stx. [44],[45]

Rasko et al, in their study identified a lead structure, LED 209 (N-phenyl-4-[[(phenylamino)thioxomenthyl]amino]-benzenesulfonamide), which selectively blocked binding of signals (AI-3/epinephrine and NE) to QseC, consequently inhibiting QseC-mediated activation of virulence gene expression. Significantly, LED 209 did not lead to killing of EHEC cell as that would have initiated Stx production. LED 209 was also not toxic to the host cell and only inhibited key virulence traits of EHEC. [46]

QseC homologs are present in at least 25 important human and plant pathogens, and AI-3/epinephrine/NE QseC receptor signaling system plays a central role in virulence of many important pathogens and qseC mutants of EHEC;  Salmonella More Details typhimurium and Francisella tularensis have been shown to be attenuated in animal models of infection. [46],[47]

Quorum sensing in gram positive bacteria

A number of gram positive organisms are known to employ Quorum sensing systems. The nature of the signal molecules used in these systems varies from those of gram negative organisms, and thus far no gram positive bacteria have been shown to produce AHLs. Gram positive Quorum sensing systems typically make use of small post-translationally processed peptide signal molecules. These peptide signals interact with the sensor element of a histidine kinase two-component signal transduction system. Quorum sensing is used to regulate the development of bacterial competence in Bacillus subtilis and Streptococcus pneumoniae, conjugation in Enterococcus faecalis and virulence in Staphylococcus aureus. [48],[49] The virulence in S. aureus is dependent on temporal expression of a diverse array of virulence factors, including both cell-associated products, such as protein A, collagen, and fibronectin-binding protein and secreted products including lipases, proteases, alpha-toxin, toxin-I, beta-hemolysin, and enterotoxin. [50] During the early stages of S. aureus infection, surface proteins involved in attachment (collagen and fibronectin binding protein) predominate. So is the case with protein involved in defense (protein A). However, once a high cell density is achieved at the site of infection, expression of S. aureus surface proteins is decreased and secreted proteins are preferentially expressed. Also, the S. aureus is known to exist in two phenotypes, an adhesive colonizer phenotype, which is tolerated by the host and the severe invasive infective phenotype that can damage the host tissues and is responsible for the disease manifestations. [41],[51] The genetic basis for this temporal gene expression depends on two pleiotropic regulatory loci called agr (accessory gene regulator) [52],[53],[54] and sar (staphylococcal accessory gene regulator). [55] The agr locus consists of two divergently transcribed operons, RNAII and RNAIII. [56],[57] The RNAII operon contains the agrBDCA genes that encode the signal transducer (AgrC) and response regulator (AgrA), and AgrB and AgrD, which are involved in generating the Quorum sensing signal molecule, the autoinducing cyclic thiolactone peptide (AIP). [52],[58] The RNAIII operon encodes a hemolysin and is itself a regulatory RNA that plays a key role in agr response. During S. aureus Quorum sensing, the AgrC signal transducer is autophosphorylated in response to the octapeptide signal molecule, which in turn leads to phosphorylation of the AgrA response regulator. [59] Phosphorylated AgrA stimulates transcription of RNAIII and this, in turn, upregulates expression of numerous S. aureus exoproteins as well as the agrBDCA locus. [56],[57] The latter leads to a rapid increase in the synthesis and export of the octapeptide signal molecule. At the second regulatory locus, the sar gene product (SarA) functions as a regulatory DNA-binding protein to induce expression of both the RNAII and RNAIII operons of agr locus. [60]

The survival of S. aureus is also dependent on genes regulated by a second QS system, RAP/TRAP. Here, the proposed AI, RNAIII activating protein (RAP) is believed to be secreted by an as yet unknown mechanism. This reenters the cell and activates the target of RAP (TRAP). The activated TRAP upregulates agr expression and promotes cellular adherence, which is essential for biofilm formation. [61]

This system has the potential to be exploited as another alternative to antibiotics. This can be accomplished by using a heptapeptide, which inhibits the activity of TRAP. The heptapeptide RNAIII inhibiting peptide (RIP) has been shown to inhibit phosphorylation of TRAP and agr expression. It was shown that RIP is effective against some strains of MRSA and a non-peptide analog of RIP, hamamelitannin, was identified which has been shown to prevent device-associated MRSA infections in a concentration dependent manner. [61],[62]

Quorum sensing and biofilm formation

Biofilms are now considered ubiquitous in the natural world. [14] In nature, bacteria are frequently found encased in polysaccharide matrix attached to a solid surface. This mode of growth, referred to as a biofilm, offers protection from environmental agents that would otherwise threaten their planktonic counterparts. Bacterial biofilms have been observed to be extremely heterogeneous, both structurally and with regard to the physiology of the bacterial cells within them. The prevailing conceptual model depicts bacterial biofilms as being made up of microcolonies, which serve as the basic unit of the greater biofilm structure. Microcolonies are hydrated structures consisting of bacterial cells enmeshed in a matrix of exopolymeric substances (EPSs). Bacteria may proliferate on the attachment surface, leading to microcolony expansion. Eventually, community growth becomes limited by substrate availability due to increased diffusion distances, and the biofilm reaches a steady state. Such mature biofilms often consist of "towers"and "mushrooms" of cells in an EPS matrix. Interstitial voids and channels separate the biofilm structures and facilitate a convective flow in order to transport nutrients to interior parts of the biofilm and remove waste products. Biofilms have become evident in many, if not most, environmental, industrial, and medical bacteria related problems. A recent public announcement from the NIH stated that more than 60% of all microbial infections involve biofilms. [22]

P. aeruginosa is an example of an organism frequently found growing in biofilms. Microscopic analysis of P. aeruginosa biofilm communities reveals that they are not just sugar-encased masses of cells, but rather distinct mushroom and stalk-like structures that contain intervening water channels to allow nutrients to flow in and waste products to flow out. In clinical setting, biofilms formed on medical devices and in bacterial infections can wreak havoc, largely because bacteria growing as biofilm are refractile to host defenses including phagocytes, antibodies, and complement. [63] Moreover, these organisms are highly resistant to antibodies making eradication by using conventional chemotherapy virtually ineffective. Thus, novel ways of preventing biofilm formation and eradicating those already established must be found. Recently, a link between biofilm formation and Quorum sensing was discovered in P. aeruginosa. Analysis of biofilms formed by a P. aeruginosa mutant deficient in the production of the las signal molecule, 3-oxo-C12-HSL, revealed a biofilm that was much thinner and lacked the three-dimensional architecture observed in that of the parent. Even more noteworthy was the fact that, while the parental biofilm was resistant to the detergent sodium dodecyl sulfate (SDS), the mutant biofilm rapidly dispersed from the underlying surface after SDS exposure. When grown in the presence of exogenous 3-oxo-C12-HSL, the mutant biofilm resembled that of the parent and was resistant to SDS. Thus, it appears that Quorum sensing plays a critical role in the formation of mature, differentiated biofilm structures. It is not known at this time whether other bacteria use Quorum sensing during biofilm formation. However, at least in case of P. aeruginosa, strategies designed to block Quorum sensing may be an effective means of preventing biofilm formation. [1]

Biofilm formation inCandida albicans

The process of biofilm formation by Candida albicans involves three main steps: the initial colonization of the substratum by the yeast cells, growth and hypha formation and the production of an extracellular matrix, primarily composed of β-1,3-glucan. The mature biofilm consists of yeasts, hyphae, and pseudohyphae; however, eventually, the yeast cells leave the biofilm. In C. albicans also the QS can modulate all stages of biofilm formation, i.e. attachment, maturation, and dispersal. [64] The best characterized QS molecule produced by C. albicans is "Farnesol," [65] which regulates the inter-conversion between its yeast and filamentous form. In in vitro experiments, farnesol has been shown to reduce the size of biofilms. The other QS molecule that may also alter biofilm development in C. albicans is "tyrosol." [66] In experiments, farnesol has been shown to repress hyphal growth by inhibiting the Ras1-adenylate cyclase-protein kinase A signaling pathway. However, the role of farnesol in multicellular population can be better understood by discovering mutants with altered farnesol response and farnesol production. [67]

Future applications of bacterialQuorum sensing

Quorum sensing is a novel target for antimicrobial therapy. The continuing emergence of multiple drug-resistant strains of bacteria has necessitated finding novel strategies for treating bacterial infections. The discovery that a wide spectrum of organisms use Quorum sensing to control virulence factor production makes it an attractive target for discovery of new anti-virulence therapeutics. The pathogenic organisms can be rendered avirulent if the Quorum sensing mechanisms that control virulence factors can be targeted. The scientific research has focused on the synthesis and characterization of AI analogs, mostly focusing on AHL-based QS systems. By virtue of the intrinsic cytotoxic activity of AHLs, they can aptly now be regarded as "small molecule toxins". [68]

The Quorum sensing pathways can be disrupted at various levels; for example at AIs and R protein levels, which have a unique specificity for one another. Non-cognate AIs typically only weakly activate or may inhibit R protein activation altogether. Therefore, analogs that bind to but do not activate R proteins could act as antagonists to prevent AI binding, which in turn would shut down the Quorum sensing cascade. The ability of AI analogs to inhibit activation of R proteins has already been demonstrated in a number of bacteria, including V. fischeri, A. tumefaciens, Chromobacterium violaceum, and Aeromonas salmonicida.[1],[69],[70],[71],[72]

Recently, enzyme from an isolate of Bacillus that is capable of degrading AHLs was discovered. This enzyme is encoded by the aiiA gene (AI inactivation) and contains two domains that are homologous to the active sites of the following metalloenzymes: glyoxalase II, metallo-B lactamase and arylsulfatase. Expression of aiiA in E. carotovora decreased generation of proteolytic enzymes and significantly reduced AI production. [73]

For finding another way of interfering with Quorum sensing, the biosynthetic pathways of some AHL molecules have been elucidated. Interrupting the AHL biosynthetic pathway and shutting down AHL synthesis, perhaps through the use of analogs of AHL precursors, would be a highly effective means of blocking the Quorum sensing cascade. [74],[75],[76],[77]

Recently, an immunotherapeutic approach for QS quenching was pioneered by generation of the anti-AHL monoclonal Ab (mAb), RS2-1G9, elicited against a synthetic 3-oxo-C12-HSL analog. The RS2-1G9 was found to efficiently suppress QS signaling in P. aeruginosa and conferred protection upon mammalian cells via neutralization of 3-oxo-C12-HSL in vitro. The monoclonal antibodies against staphylococcal AIPs have been developed by using a hapten in which the hydrolytically labile thiolactone was replaced with a more stable lactone moiety. The mAbs thus developed were evaluated both in vitro and in vivo and were shown to possess potent Quorum quenching abilities, including the protection of mice from an otherwise lethal S. aureus infection. [68],[78],[79]

Recently, a novel Bacillus spp. strain, designated Quorum sensing Inhibitor-1 (QSI-1) by the researchers was isolated and identified from the intestine of the fish, Carassius auratus gibelio. The isolated QSI-1 is capable of utilizing AHL molecules as the sole source of energy and possesses at least one type of AHL degrading enzymes capable of degrading the AHLs of fish pathogen, Aeromonas hydrophila, thus significantly decreasing the production of its extracellular proteases, in turn increasing the survival rate of infected fish. Thus, perhaps this QSI-1 strain be used as a probiotic in aquaculture. [80]

   Conclusion Top

The ability to coordinate behavior in a cell-density-dependent fashion has several obvious advantages. In the case of pathogenic microorganisms, the regulation of virulence determinants throughout the infection process is believed to play an important role in pathogenicity. Evading host defenses is a major goal of pathogens, and Quorum sensing equips these bacteria to appropriately time the expression of immune evading machinery. Using Quorum sensing, bacteria can amass a high cell density before virulence determinants are expressed, and in doing so, the bacteria are able to make a concerted attack and produce ample virulence factors to overwhelm the host defenses. As the list of bacteria that employ Quorum sensing systems continues to grow, so does the number of possibilities for exploiting these regulatory mechanisms. Because many important animal and plant pathogens use Quorum sensing to regulate virulence, strategies designed to interfere with these signaling systems will likely have broad applicability for biological control of disease causing organisms. In the future, it will be intriguing to see whether additional human pathogens utilize Quorum sensing as part of their pathogenic lifestyle and, if so, whether production of the signal molecules, AHL or otherwise, can be exploited to control infections.

   References Top

1.Vasil ML. NA Microarrays in Analysis of Quorum sensing: Strengths and Limitations. J Bacteriol 2003;185:2061-5.  Back to cited text no. 1
2.De Kievit TR, Iglewski BH. Bacterial Quorum sensing in Pathogenic Relationships. Infect Immun 2000;68:4839-49.  Back to cited text no. 2
3.Sifri CD. Quorum sensing: Bacteria Talk Sense. Clin Infect Dis 2008;47:1070-6.  Back to cited text no. 3
4.Schuster M, Lostroh CP, Ogi T, Greenberg EP. Identification, timing, and signal specificity of Pseudomonas aeruginosa quorum-controlled genes: A transcriptome analysis. J Bacteriol 2003;185:2066-79.  Back to cited text no. 4
5.Wagner VE, Bushnell D, Passador L, Brooks AI, Iglewski BH. Microarrayanalysis of Pseudomonas aeruginosa Quorum sensing regulons: Effects of growth phase and environment. J Bacteriol 2003;185:2080-95.  Back to cited text no. 5
6.Dunman PM, Murphy E, Haney S, Palacios D, Tucker-Kellogg G, Wu S, et al. Transcription profiling-based identification of Staphylococcus aureus genes regulated by the agr and/ or sarA loci. J Bacteriol 2001;183:7341-53.  Back to cited text no. 6
7.Arevalo-Ferro C, Hentzer M, Reil G, Görg A, Kjelleberg S, Givskov M, et al. Identification of Quorum sensing regulated proteins in the opportunistic pathogen Pseudomonas aeruginosa by proteomics. Environ Microbiol 2003;5:1350-69.  Back to cited text no. 7
8.Eberhard A. Inhibition and activation of bacterial luciferase synthesis. J Bacteriol 1972;109:1101-5.  Back to cited text no. 8
9.Kempner ES, Hanson FE. Aspects of light production by Photobacterium fischeri. J Bacteriol 1968;95:975-9.  Back to cited text no. 9
10.Nealson KH, Platt T, Hastings JW. Cellular control of the synthesis and activity of the bacterial luminescent system. J Bacteriol 1970;104:313-22.  Back to cited text no. 10
11.Pearson JP. Early Activation of Quorum sensing. J Bacteriol 2002;184:2569-71.  Back to cited text no. 11
12.Eberhard A, Burlingame AL, Eberhard C, Kenyon GL, Nealson KH, Oppenheimer NJ. Structural identification of autoinducer of Photobacterium fischeri luciferase. Biochemistry 1981;20:2444-9.  Back to cited text no. 12
13.Fuqua WC, Winans SC, Greenberg EP. Quorum sensing in bacteria: The LuxR-LuxI family of cell density-responsive transcriptional regulators. J Bacteriol 1994;176:269-75.  Back to cited text no. 13
14.Kuo A, Callahan SM, Dunlap PV. Modulation of luminescence operon expression by N-octanoyl-L-homoserine lactone in ainS mutants of Vibrio fischeri. J Bacteriol 1996;178:971-6.  Back to cited text no. 14
15.Flavier AB, Clough SJ, Schell MA, Denny TP. Identification of 3-hydroxypalmitic acid methyl ester as a novel autoregulator controlling virulence in Ralstonia solanacearum. Mol Microbiol 1997;26:251-9.  Back to cited text no. 15
16.Barber CE, Tang JL, Feng JX, Pan MQ, Wilson TJ, Slater H, et al. A novel regulatory system required for pathogenicity of Xanthomonas campestris is mediated by a small diffusible signal molecule. Mol Microbiol 1997;24:555-66.  Back to cited text no. 16
17.Pesci EC, Milbank JB, Pearson JP, McKnight S, Kende AS, Greenberg EP, et al. Quinolone signaling in the cell-to-cell communication system of Pseudomonas aeruginosa. Proc Natl Acad Sci USA 1999;96:11229-34.  Back to cited text no. 17
18.Gallagher LA, McKnight SL, Kuznetsova MS, Pesci EC, Manoil C. Functions required for extracellular quinolone signaling by Pseudomonas aeruginosa. J Bacteriol 2002;184:6472-80.  Back to cited text no. 18
19.Déziel E, Lépine F, Milot S, He J, Mindrinos MN, Tompkins RG, et al. Analysis of Pseudomonas aeruginosa4-hydroxy-2-alkylquinolines (HAQs) reveals a role for 4-hydroxy-2-heptylquinoline in cell-to-cell communication. Proc Natl Acad Sci USA 2004;101:1339-44.  Back to cited text no. 19
20.Gamard P, Sauriol F, Benhamou N, Belanger RR, Paulitz TC. Novel butyrolactones with antifungal activity produced by Pseudomonas aureofaciens strain 63-28. J Antibiot 1997;50:742-9.  Back to cited text no. 20
21.Fergie JE, Shema SJ, Lott L, Crawford R, Patrick CC. Pseudomonas aeruginosa bacteremia in immunocompromised children: Analysis of factors associated with a poor outcome. Clin Infect Dis 1994;18:390-4.  Back to cited text no. 21
22.Mendelson MH, Gurtman A, Szabo S, Neibart E, Meyers BR, Policar M, et al. Pseudomonas aeruginosa bacteremia in patients with AIDS. Clin Infect Dis 1994;18:886-95.  Back to cited text no. 22
23.Brewer SC, Wunderink RG, Jones CB, Leeper KV. Ventilator-associated pneumonia due to Pseudomonas aeruginosa. Chest 1996;109:1019-29.  Back to cited text no. 23
24.Dunn M, Wunderink RG. Ventilator-associated pneumonia caused by Pseudomonas infection. Clinics Chest Med 1995;16:95-109.  Back to cited text no. 24
25.Gambello MJ, Iglewski BH. Cloning and characterization of the Pseudomonas aeruginosa lasR gene, a transcriptional activator of elastase expression. J Bacteriol 1991;173:3000-9.  Back to cited text no. 25
26.Passador L, Cook JM, Gambello MJ, Rust L, Iglewski BH. Expression of Pseudomonas aeruginosa virulence genes requires cell-to-cell communication. Science 1993;260:1127-30.  Back to cited text no. 26
27.Brint JM, Ohman DE. Synthesis of multiple exoproducts in Pseudomonas aeruginosa is under the control of RhlR-RhlI, another set of regulators in strain PAO1 with homology to the autoinducer-responsive LuxR-LuxI family. J Bacteriol 1995177:7155-63.  Back to cited text no. 27
28.Latifi A, Winson MK, Foglino M, Bycroft BW, Stewart GS, Lazdunski A, et al. Multiple homologues of LuxR and LuxI control expression of virulence determinants and secondary metabolites through Quorum sensing in Pseudomonas aeruginosa PAO1. Mol Microbiol 1995;17:333-43.  Back to cited text no. 28
29.Ochsner UA, Koch AK, Fiechter A, Reiser J. Isolation and characterization of a regulatory gene affecting rhamnolipid biosurfactant synthesis in Pseudomonas aeruginosa. J Bacteriol 1994;176:2044-54.  Back to cited text no. 29
30.Ochsner UA, Reiser J. Autoinducer-mediated regulation of rhamnolipid biosurfactant synthesis in Pseudomonas aeruginosa. Proc Natl Acad Sci USA 1995;92:6424-8.  Back to cited text no. 30
31.Pearson JP, Gray KM, Passador L, Tucker KD, Eberhard A, Iglewski BH, et al. Structure of the autoinducer required for expression of Pseudomonas aeruginosa virulence genes. Proc Natl Acad Sci USA 1994;91:197-201.  Back to cited text no. 31
32.Whiteley M, Lee KM, Greenberg EP. Identification of genes controlled by Quorum sensing in Pseudomonas aeruginosa. Proc Natl Acad Sci USA 1996;96:13904-9.  Back to cited text no. 32
33.Whiteley M, Parsek MR, Greenberg EP. Regulation of Quorum sensing by RpoS in Pseudomonas aeruginosa. J Bacteriol 2000;182:4356-60.  Back to cited text no. 33
34.Chugani SA, Whiteley M, Lee KM, D'Argenio D, Manoil C, Greenberg EP. QscR, a modulator of Quorum sensing signal synthesis and virulence in Pseudomonas aeruginosa. Proc Natl Acad Sci USA 2001;98:2752-57.  Back to cited text no. 34
35.Pessi G, Williams F, Hindle Z, Heurlier K, Holden MT, Cámara M, et al. The global posttranscriptional regulator RsmA modulates production of virulence determinants and N-acylhomoserine lactones in Pseudomonas aeruginosa. J Bacteriol 2001;183:6676-83.  Back to cited text no. 35
36.van Delden C, Comte R, Bally AM. Stringent response activates Quorum sensing and modulates cell density-dependent gene expression in Pseudomonas aeruginosa. J Bacteriol 2001;183:5376-84.  Back to cited text no. 36
37.Tang HB, DiMango E, Bryan R, Gambello M, Iglewski BH, Goldberg JB, et al. Contribution of specific Pseudomonas aeruginosa virulence factors to pathogenesis of pneumonia in a neonatal mouse model of infection. Infect Immun 1996;64:37-43.  Back to cited text no. 37
38.Pearson JP, Feldman M, Iglewski BH, Prince A. Pseudomonas aeruginosa cell-to-cell signaling is required for virulence in a model of acute pulmonary infection. Infect Immun 2000;68:4331-4.  Back to cited text no. 38
39.Rumbaugh KP, Griswold JA, Hamood AN. Contribution of the regulatory gene lasR to the pathogenesis of Pseudomonas aeruginosa infection of burned mice. J Burn Care Rehabil 1999;20:42-9.  Back to cited text no. 39
40.Rumbaugh KP, Griswold JA, Iglewski BH, Hamood AN. Contribution of Quorum sensing to the virulence of Pseudomonas aeruginosa in burn wound infections. Infect Immun 1999;67:5854-62.  Back to cited text no. 40
41.Njoroge J, Sperandio V. Jamming bacterial communication: New approaches for the treatment of infectious diseases. EMBO Mol Med 2009;1:201-10.  Back to cited text no. 41
42.Kaper JB, Nataro JP, Mobley HL. Pathogenic Escherichia coli. Nat Rev Microbiol 2004;2:123-40.  Back to cited text no. 42
43.Kimmitt PT, Harwood CR, Barer MR. Toxin gene expression by shiga toxin-producing Escherichia coli: The role of antibiotics and the bacterial SOS response. Emerg Infect Dis 2000;6:458-65.  Back to cited text no. 43
44.Sperandio V, Torres AG, Jarvis B, Nataro JP, Kaper JB. Bacteria-host communication: The language of hormones. Proc Natl Acad Sci USA 2003;100:8951-6.  Back to cited text no. 44
45.Walters M, Sperandio V. Quorum sensing in Escherichia coli and Salmonella. Int J Med Microbiol 2006;296:125-31.  Back to cited text no. 45
46.Rasko DA, Moreira CG, Li de R, Reading NC, Ritchie JM, Waldor MK, et al. Targeting QseC signaling and virulence for antibiotic development. Science 2008;321:1078-80.  Back to cited text no. 46
47.Wagner C, Zimmermann S, Brenner-Weiss G, Hug F, Prior B, Obst U, et al. The Quorum sensing molecule N-3-oxododecanoyl homoserine lactone (3OC12-HSL) enhances the host defence by activating human polymorphonuclear neutrophils (PMN). Anal Bioanal Chem 2007;387:481-7.  Back to cited text no. 47
48.Dunny GM, Hirt H, Erlandsen S. Multiple roles for enterococcal sex pheromone peptides in conjugation, plasmid maintenance and pathogenesis. In: England R, Hobbs G, Bainton N, Roberts DM, editors. Microbial signalling and communication. Cambridge, United Kingdom: University Press; 1999. p. 117-38.  Back to cited text no. 48
49.Kleerebezem M, Quadri LE, Kuipers OP, De Vos WM. Quorum sensing by peptide pheromones and two component signal transduction systems in Gram positive bacteria. Mol Microbiol 1997;24:895-904.  Back to cited text no. 49
50.Dunny GM, Leonard AB. Cell-cell communication in Gram positive bacteria. Annu Rev Microbiol 1997;51:527-64.  Back to cited text no. 50
51.George EA, Muir TW. Molecular mechanisms of agr Quorum sensing in virulent staphylococci. Chembiochem 2007;8:847-55.  Back to cited text no. 51
52.Geisinger E, Muir TW, Novick RP. agr receptor mutants reveal distinct modes of inhibition by staphylococcal autoinducing peptides. Proc Natl Acad Sci U S A 2009;106:1216-21.  Back to cited text no. 52
53.Morfeldt E, Janzon L, Arvidson S, Lofdahl S. Cloning of a chromosomal locus (exp) which regulates the expression of several exoprotein genes in Staphylococcus aureus. Mol Gen Genet 1988;211:435-40.  Back to cited text no. 53
54.Recsei P, Kreiswirth B, O'Reilly M, Schlievert P, Gruss A, Novick RP. Regulation of exoprotein gene expression in Staphylococcus aureus by agr. Mol Gen Genet 1986;202:58-61.  Back to cited text no. 54
55.Cheung AL, Koomey JM, Butler CA, Projan SJ, Fischetti VA. Regulation of exoprotein expression in Staphylococcus aureus by a locus (sar) distinct from agr. Proc Natl Acad Sci USA 1992;89:6462-6.  Back to cited text no. 55
56.Ji G, Beavis RC, Novick RP. Cell density control of staphylococcal virulence mediated by an octapeptide pheromone. Proc Natl Acad Sci USA 1995;92:12055-9.  Back to cited text no. 56
57.Ji G, Beavis RC, Novick RP. Bacterial interference caused by autoinducing peptide variants. Science 1997;276:2027-30.  Back to cited text no. 57
58.Novick RP, Projan SJ, Kornblum J, Ross HF, Ji G, Kreiswirth B, et al. The agr P2 operon: An autocatalytic sensory transduction system in Staphylococcus aureus. Mol Gen Genet 1995;248:446-58.  Back to cited text no. 58
59.Lina G, Jarraud S, Ji G, Greenland T, Pedraza A, Etienne J, et al. Transmembrane topology and histidine protein kinase activity of AgrC, the agr signal receptor in Staphylococcus aureus. Mol Microbiol 1998;28:655-62.  Back to cited text no. 59
60.Rechtin TM, Gillaspy AF, Schumacher Ma, Brennan RG, Smeltzer MS, Hurlburt BK. Characterization of the SarA virulence gene regulator of Staphylococcus aureus. Mol Microbiol 1999;33:307-16.  Back to cited text no. 60
61.Novick RP. Autoinduction and signal transduction in the regulation of staphylococcal virulence. Mol Microbiol 2003;48:1429-49.  Back to cited text no. 61
62.Kiran MD, Giacometti A, Cirioni O, Balaban N. Suppression of biofilm related, device-associated infections by staphylococcal Quorum sensing inhibitors. Int J Artif Organs 2008;31:761-70.  Back to cited text no. 62
63.Costerton JW, Stewart PS, Greenberg EP. Bacterial biofilms: A common cause of persistant infections. Science 1999;284:1318-22.  Back to cited text no. 63
64.Deveau A, Hogan DA. Linking Quorum sensing regulation and biofilm formation by Candida albicans. Methods Mol Biol 2011;692:219-33.  Back to cited text no. 64
65.Hornby JM, Jensen EC, Lisec AD, Tasto JJ, Jahnke B, Shoemaker R, et al. Quorum sensing in the dimorphic fungus Candida albicans is mediated by farnesol. Appl Environ Microbiol 2001;67:2982-92.  Back to cited text no. 65
66.Chen H, Fujita M, Feng Q, Clardy J, Fink GR. Tyrosol is a Quorum sensing molecule in Candida albicans. Proc Natl Acad Sci USA 2004;101:5048-52.  Back to cited text no. 66
67.Navarathna DH, Hornby JM, Krishnan N, Parkhurst A, Duhamel GE., Nickerson KW. Effect of farnesol on a mouse model of systemic candidiasis, determined by use of a DPP3 knockout mutant of Candida albicans. Infect Immun 2007;75:1609-18.  Back to cited text no. 67
68.Kaufmann GF, Park J, Mayorov AV, Kubitz DM, Janda KD. Generation of Quorum quenching antibodies. Methods Mol Biol 2011;692:299-311.  Back to cited text no. 68
69.Milton DL, Hardman A, Camara M, Chhabra SR, Bycroft BW, Stewart GS, et al. Quorum sensing in Vibrio anguillarum: Characterization of the vanI/vanR locus and identification of the autoinducer N-(3-oxododecanoyl)-L-homoserine lactone. J Bacteriol 1997;179:3004-12.  Back to cited text no. 69
70.Schaefer AL, Hanzelka BL, Eberhard A, Greenberg EP. Quorum sensing in Vibrio fischeri: Probing autoinducer-LuxR interactions with autoinducer analogs. J Bacteriol 1996;178:2897-901.  Back to cited text no. 70
71.Swift S, Karlyshev AV, Fish L, Durant EL, Winson MK, Chhabra SR, et al. Quorum sensing in Aeromonas hydrophila and Aeromonas salmonicida: Identification of the LuxRI homologues AhyRI and AsaRI and their cognate signal molecules. J Bacteriol 1997;179:5271-81.  Back to cited text no. 71
72.Zhu J, Beaber JW, Moré MI, Fuqua C, Eberhard A, Winans SC. Analogs of the autoinducer 3-oxooctanoylhomoserine lactone strongly inhibit activity of the TraR protein of Agrobacterium tumefaciens. J Bacteriol 1998;180:5398-405.  Back to cited text no. 72
73.Dong YH, Xu JL, Li XZ, Zhang LH. AiiA, an enzyme that inactivates the acylhomoserine lactone Quorum sensing signal and attenuates the virulence of Erwinia carotovora. Proc Natl Acad Sci USA 2000;97:3526-31.  Back to cited text no. 73
74.Hanzelka BL, Greenberg EP. Quorum sensing in Vibrio fischeri: Evidence that S-adenosyl methionine is the amino acid substrate for autoinducer synthesis. J Bacteriol 1996;178:5291-4.  Back to cited text no. 74
75.Jiang Y, Camara M, Chhabra SR, Hardie KR, Bycroft BW, Lazdunski A, et al. In vitro biosynthesis of the Pseudomonas aeruginosa Quorum sensing signal molecule, N-butanoyl-L-homoserine lactone. Mol Microbiol 1998;28:193-204.  Back to cited text no. 75
76.Moré MI, Finger LD, Stryker JL, Fuqua C, Eberhard A, Winans SA. Enzymatic synthesis of a Quorum sensing autoinducer through use of defined substrates. Science 1996;272:1655-8.  Back to cited text no. 76
77.Schaefer AL, Val DL, Hanzelka BL, Cronan JE, Greenberg EP. Generation of cell-to-cell signals in Quorum sensing: Acylhomoserine synthase activity of a purified Vibrio fischeri LuxI protein. Proc Natl Acad Sci USA 1996;93:9505-9.  Back to cited text no. 77
78.Kaufmann GF, Sartorio R, Lee SH, Mee JM, Altobell LJ 3 rd , Kujawa DP, et al. Antibody interference with N-acyl homoserine lactone-mediated bacterial Quorum sensing. J Am Chem Soc 2006;128:2802-3.  Back to cited text no. 78
79.Park J, Jagasia R, Kaufmann GF, Mathison JC, Ruiz DI, Moss JA, et al. Infection control by antibody Disruption of bacterial Quorum sensing signaling. Chem Biol 2007;14:1119-27.  Back to cited text no. 79
80.Chu W, Lu F, Zhu W, Kang C. Isolation and characterization of new potential probiotic bacteria based on Quorum sensing system. J Appl Microbiol 2010;110:202-8.  Back to cited text no. 80

This article has been cited by
1 Pantoeasp. Isolated from Tropical Fresh Water ExhibitingN-Acyl Homoserine Lactone Production
Wen-Si Tan,Nina Yusrina Muhamad Yunos,Pui-Wan Tan,Nur Izzati Mohamad,Tan-Guan-Sheng Adrian,Wai-Fong Yin,Kok-Gan Chan
The Scientific World Journal. 2014; 2014: 1
[Pubmed] | [DOI]
2 Mechanisms of quorum sensing and strategies for quorum sensing disruption in aquaculture pathogens
J Zhao,M Chen,CS Quan,SD Fan
Journal of Fish Diseases. 2014; : n/a
[Pubmed] | [DOI]
3 Inhibitory effect of N-ethyl-3-amino-5-oxo-4-phenyl-2,5-dihydro-1H-pyrazole-1-carbothioamide on Haemophilus spp. planktonic or biofilm-forming cells
Urszula Kosikowska,Anna Malm,Monika Pitucha,Barbara Rajtar,Malgorzata Polz-Dacewicz
Medicinal Chemistry Research. 2013;
[Pubmed] | [DOI]
4 Studies on bacterial pathogens isolated from diseased torafugu (Takifugu rubripes) cultured in marine industrial recirculation aquaculture system in Shandong Province, China
Fushun Wu,Kaihao Tang,Meng Yuan,Xiaochong Shi,Qismat Shakeela,Xiao-Hua Zhang
Aquaculture Research. 2013; : n/a
[Pubmed] | [DOI]
5 Pseudomonas aeruginosa: new insights into pathogenesis and host defenses
Shaan L. Gellatly,Robert E.W. Hancock
Pathogens and Disease. 2013; 67(3): 159
[Pubmed] | [DOI]
6 Endemic Malagasy Dalbergia species inhibit quorum sensing in Pseudomonas aeruginosa PAO1
T. Rasamiravaka,A. Jedrzejowski,M. Kiendrebeogo,S. Rajaonson,D. Randriamampionona,C. Rabemanantsoa,A. Andriantsimahavandy,A. Rasamindrakotroka,P. Duez,M. El Jaziri,O. M. Vandeputte
Microbiology. 2013; 159(Pt_5): 924
[Pubmed] | [DOI]
7 Applications of small molecule activators and inhibitors of quorum sensing in Gram-negative bacteria
Warren R.J.D. Galloway,James T. Hodgkinson,Steven Bowden,Martin Welch,David R. Spring
Trends in Microbiology. 2012; 20(9): 449
[Pubmed] | [DOI]


    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article
    Historical Aspects

 Article Access Statistics
    PDF Downloaded1195    
    Comments [Add]    
    Cited by others 7    

Recommend this journal