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Year : 2012  |  Volume : 2  |  Issue : 4  |  Page : 97-99

Quorum sensing: A nobel target for antibacterial agents

Department of Pharmacy, GRD (PG) Institute of Management and Technology, Dehradun, Uttarakhand, India

Date of Web Publication19-Apr-2013

Correspondence Address:
Mohammad Asif
Department of Pharmacy, GRD (PG) Institute of Management and Technology, Dehradun - 248 009, Uttarakhand
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2231-0770.110743

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How to cite this article:
Asif M, Acharya M. Quorum sensing: A nobel target for antibacterial agents. Avicenna J Med 2012;2:97-9

How to cite this URL:
Asif M, Acharya M. Quorum sensing: A nobel target for antibacterial agents. Avicenna J Med [serial online] 2012 [cited 2020 Oct 28];2:97-9. Available from: https://www.avicennajmed.com/text.asp?2012/2/4/97/110743

   Introduction Top

Traditionally, it was believed that cell-to-cell communication and social cooperation only present in the eukaryotes. Recently, it has been revealed that this signaling process also present in Prokaryotes. [1] Communication between bacterial cells termed as quorum sensing (QS). [2] QS has not only been described between cells of the same species, but also between different species and between bacteria and higher organisms. The term QS was first used in a review by Fuqua et al., which essentially reflected the minimum threshold level of individual cell mass required initiating a concerted population response. The first incidence of such a biological phenomenon came to light with the discovery of luminescence produced by certain marine bacteria such as Vibrio fischeri and Vibrio harveyi. [3] It is now appreciated that bacteria are highly interactive and exhibit a number of social behaviors, such as swarming motility, conjugal plasmid transfer, antibiotic resistance, biofilm maturation, and virulence. [4],[5],[6] Many of these behaviors are regulated by diverse QS systems, which are found in both Gram-negative and Gram-positive bacteria. Bacteria are sensitive to an increase in population density and respond quickly and coordinately by inducting certain sets of genes. This mode of regulation, known as QS, is based on the interaction of low-molecular-weight signal molecules called auto-inducers (AIs) or pheromones with a sensor kinase and response regulator to activate or repress gene expression. QS systems are considered to be global regulators and play a key role in controlling many metabolic processes in the cell, including, bacterial virulence. These systems offer attractive targets for a novel class of antibacterial drugs, capable of inducing chemical attenuation of pathogenicity. [7] The subsequent discovery of compounds that inhibit cell-to-cell communication, dubbed anti-QS agents could provide a novel method of combating infection. [4],[8]

   Quorum Sensing Top

QS is a population-dependent phenomenon first characterized in the 1970s in luminescent marine species of Vibrio. [9] The ability to sense the size of a bacterial population is mediated through small signaling molecules or AIs. [10],[11] These molecules are constantly produced and received at a basal level by bacterial cells. With high population density, there is a surplus of signaling molecules in the environment. These signals diffuse back in to the cell where they facilitate the regulation of gene expression. [10] QS systems are ubiquitous among bacteria, and have since been found to regulate diverse functions such as luminescence, biofilm formation, antibiotic and virulence factor generation, pigment production, plant-microbe interactions, and motility. [4],[5],[6] Although, there are a number of different QS systems, [12] the most widely studied paradigm is based on the Lux system of Vibrio fisheri and V. harveyi. [13],[14] This QS phenomenon involves a three component-system: a freely diffusible signal, a synthase to make this signal, and a regulator that interacts in conjunction with the signal to regulate gene expression. The main signaling molecules produced by Gram-negative bacteria are acyl-homoserine lactones (AHLs). [15] They differ in the length of their side chains and substitution at the C3 carbon, based on the organism that produces them. [16],[17]

AHL-mediated QS systems based on the LuxI/LuxR (LuxI/LuxR, is the counterpart in marine bacteria of the th luciferase system. They mediate bioluminescence, and are products of genes regulated by the lux operon. Light production in V. fischeri is controlled by two regulatory proteins named LuxI and LuxR. LuxI is the autoinducer synthase that is responsible for the synthesis of the acyl-HSL autoinducer. LuxR is a transcriptional activator protein that, when bound to autoinducer, promotes transcription of the luciferase structural operon luxCDABE) paradigm have been characterized in human pathogens such as Pseudomonas aeruginosa, [18]  Yersinia More Details pseudotuberculosis, [19] and  Escherichia More Details coli, [20] as well as plant associated bacteria such as Rhizobium leguminosarum, [21] Ralstonia solanacearum, and Erwinia carotovora. [22] In all cases, these systems can regulate virulence. Thus, the discovery of QS has given us a new target-a new way to attack and attenuate bacterial pathogenicity.

   Anti-QS Top

The subsequent discovery of compounds that inhibit cell-to-cell communication, dubbed anti-QS agents could provide a novel method of combating infection. [4],[8] Anti-QS agents were first characterized in the red marine alga, Delisea pulchura. [23] This alga was investigated for its anti-fouling properties, and was found to contain halogenated furanones, compounds, which block AHLs via competitive inhibition and destabilization of LuxR. [24]

QS inhibitions

There are a number of ways to inhibit cell-cell communication including competitive inhibition, signal binding, degradation of the signaling molecule, and inhibition of upstream precursors or genetic regulation systems. Success has been seen with competitive inhibition in the case of the furanones, however, many other QS antagonists have since been discovered. [8] These antagonists are based on the C12-AHL structure and cause a reduction in LasR activity. AHL-antibodies have also been developed to suppress QS through signal binding. [25],[26] A C12-AHL-protein conjugate was able to successfully inhibit lasB expression, and a similar molecule with extremely high binding affinity for C12-AHL was recently crystallized and characterized. [25] Blocking S-adenosyl methionine or the fatty acid precursors necessary to synthesize AHLs leads to decreased production of C12-AHL by LasI. [27] Of course, genetic modification of up-stream global regulators such as Vfr and GacA has also been shown to greatly reduce QS activity and the subsequent production of virulence factors. [28],[29] Numerous bacteria including Bacillus sp., Variovorax paradoxus, Arthrobacter sp., and Agrobacterium tumefaciens produce lactonases-enzymes that cleave and deactivate the lactone ring of various AHLs. [30],[31] Lactonase expression in P. aeruginosa, results in a significant decrease in AHL production and virulence factor expression. [4],[32]

   Conclusion Top

Interest is growing in practical applications of anti-QS especially, when faced with increased incidence of drug failure due to the large number of pathogenic bacteria developing resistance to available antibiotics. It has been suggested that targeting pathogenesis instead of killing the organism may provide less selective pressure and therefore, decreased emergence of resistant strains.

   References Top

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4.Hentzer M, Givskov M. Pharmacological inhibition of quorum sensing for the treatment of chronic bacterial infections. J Clin Invest 2003;112:1300-7.  Back to cited text no. 4
5.Rasmussen TB, Bjarnsholt T, Skindersoe ME, Hentzer M, Kristoffersen P, Köte M, et al. Screening for quorum-sensing inhibitors (QSI) by use of a novel genetic system, the QSI selector. J Bacteriol 2005;187:1799-814.  Back to cited text no. 5
6.Shih PC, Huang CT. Effects of quorum-sensing deficiency on Pseudomonas aeruginosa biofilm formation and antibiotic resistance. J Antimicrob Chemother 2002;49:309-14.  Back to cited text no. 6
7.Fatma AA, Eman ME, Heba AM. New targets for antibacterial agents. Biotechnol Mol Biol Rev 2008;3:046-57.  Back to cited text no. 7
8.Smith RS, Iglewski BH. Pseudomonas aeruginosa quorum sensing as a potential antimicrobial target. J Clin Invest 2003;112:1460-5.  Back to cited text no. 8
9.Zhang LH, Dong YH. Quorum sensing and signal interference: Diverse implications. Mol Microbiol 2004;53:1563-71.  Back to cited text no. 9
10.Hastings JW, Greenberg EP. Quorum sensing: The explanation of a curious phenomenon reveals a common characteristic of bacteria. J Bacteriol 1999;181:2667-8.  Back to cited text no. 10
11.Schauder S, Shokat K, Surette MG, Bassler BL. The LuxS family of bacterial autoinducers: Biosynthesis of a novel quorum-sensing signal molecule. Mol Microbiol 2001;41:463-76.  Back to cited text no. 11
12.Henke JM, Bassler BL. Quorum sensing regulates type III secretion in Vibrio harveyi and Vibrio parahaemolyticus. J Bacteriol 2004;186:3794-805.  Back to cited text no. 12
13.Bassler BL, Wright M, Showalter RE, Silverman MR. Intercellular signalling in Vibrio harveyi: Sequence and function of genes regulating expression of luminescence. Mol Microbiol 1993;9:773-86.  Back to cited text no. 13
14.Stevens AM, Greenberg EP. Quorum sensing in Vibrio fischeri: Essential elements for activation of the luminescence genes. J Bacteriol 1997;179:557-62.  Back to cited text no. 14
15.Fuqua C, Greenberg EP. Self-perception in bacteria: Quorum sensing with acylated homoserine lactones. Curr Opin Microbiol 1998;1:183-9.  Back to cited text no. 15
16.Marketon MM, Glenn SA, Eberhard A, González JE. Quorum sensing controls exopolysaccharide production in Sinorhizobium meliloti. J Bacteriol 2003;185:325-31.  Back to cited text no. 16
17.Whitehead NA, Barnard AM, Slater H, Simpson NJ, Salmond GP. Quorum-sensing in Gram-negative bacteria. FEMS Microbiol Rev 2001;25:365-404.  Back to cited text no. 17
18.Pessi G, Haas D. Transcriptional control of the hydrogen cyanide biosynthetic genes hcnABC by the anaerobic regulator ANR and the quorum-sensing regulators LasR and RhlR in Pseudomonas aeruginosa. J Bacteriol 2000;182:6940-9.  Back to cited text no. 18
19.Atkinson S, Throup JP, Stewart GS, Williams P. A hierarchical quorum-sensing system in Yersinia pseudotuberculosis is involved in the regulation of motility and clumping. Mol Microbiol 1999;33:1267-77.  Back to cited text no. 19
20.Surette MG, Bassler BL. Quorum sensing in Escherichia coli and Salmonella typhimurium. Proc Natl Acad Sci U S A 1998;95:7046-50.  Back to cited text no. 20
21.Rodelas B, Lithgow JK, Wisniewski-Dye F, Hardman A, Wilkinson A, Economou A, et al. Analysis of quorum-sensing-dependent control of rhizosphere-expressed (rhi) genes in Rhizobium leguminosarum bv. viciae. J Bacteriol 1999;181:3816-23.  Back to cited text no. 21
22.Von Bodman SB, Bauer WD, Coplin DL. Quorum sensing in plant-pathogenic bacteria. Annu Rev Phytopathol 2003;41:455-82.  Back to cited text no. 22
23.Manefield M, de Nys R, Kumar N, Read R, Givskov M, Steinberg P, et al. Evidence that halogenated furanones from Delisea pulchra inhibit acylated homoserine lactone (AHL)-mediated gene expression by displacing the AHL signal from its receptor protein. Microbiology 1999;145:283-91.  Back to cited text no. 23
24.Manefield M, Rasmussen TB, Henzter M, Andersen JB, Steinberg P, Kjelleberg S, et al. Halogenated furanones inhibit quorum sensing through accelerated LuxR turnover. Microbiology 2002;148:1119-27.  Back to cited text no. 24
25.Debler EW, Kaufmann GF, Kirchdoerfer RN, Mee JM, Janda KD, Wilson IA. Crystal structures of a quorum-quenching antibody. J Mol Biol 2007;368:1392-402.  Back to cited text no. 25
26.Smith RS, Iglewski BH. P. aeruginosa quorum-sensing systems and virulence. Curr Opin Microbiol 2003;6:56-60.  Back to cited text no. 26
27.Hoang HH, Becker A, González JE. The LuxR homolog ExpR, in combination with the Sin quorum sensing system, plays a central role in Sinorhizobium meliloti gene expression. J Bacteriol 2004;186:5460-72.  Back to cited text no. 27
28.Kociolek MG. Quorum-Sensing Inhibitors and Biofilms. Anti-infective Agents in Med Chem 2009;8:315-26.   Back to cited text no. 28
29.Riemann H, Himathongkham S, Willoughby D, Tarbell R, Breitmeyer R. A survey for Salmonella by drag swabbing manure piles in California egg ranches. Avian Dis 1998;42:67-71.  Back to cited text no. 29
30.Carlier A, Uroz S, Smadja B, Fray R, Latour X, Dessaux Y, et al. The Ti plasmid of agrobacterium tumefaciens harbors an attM-paralogous gene, aiiB, also encoding N-Acyl homoserine lactonase activity. Appl Environ Microbiol 2003;69:4989-93.  Back to cited text no. 30
31.Zahin M, Hasan S, Aqil F, Khan MS, Husain FM, Ahmad I. Screening of certain medicinal plants from India for their anti-quorum sensing activity. Indian J Exp Biol 2010;48:1219-24.  Back to cited text no. 31
32.Zeng Z, Qian L, Cao L, Tan H, Huang Y, Xue X, et al. Virtual screening for novel quorum sensing inhibitors to eradicate biofilm formation of Pseudomonas aeruginosa. Appl Microbiol Biotechnol 2008;79:119-26.  Back to cited text no. 32

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