Pakistan Veterinary Journal

ISSN: 0253-8318 (PRINT), 2074-7764 (ONLINE)

Accessible at: www.pvj.com.pk
REVIEW ARTICLE
The Role of Chemical and Herbal Antipathogenic Compounds in the Prevention of Quorum
Sensing-Dependent Pathogenicity of Pseudomonas aeruginosa - A Review
Hira Hameed and Saiyed I Ahmed*

Institute of Microbiology, University of Agriculture, Faisalabad-38040, Pakistan

*Corresponding author: ahmedsiai@yahoo.com

ARTICLE HISTORY (14-237) ABSTRACT

Received: May 16, 2014 Pseudomonas aeruginosa is an opportunistic pathogen of humans, animals as well
Revised: June 28, 2014 as of plants and the most common Gram-negative bacterium found in nosocomial
Accepted: August 10, 2014 infections. Pseudomonas associated biofilms are highly tolerant to lethal doses of
Key words: antibiotics. Recent discoveries of quorum quenching mechanisms use quorum
Antipathogenic compounds sensing as a potential antimicrobial target. In this review we discuss the efficacy of
Pseudomonas aeruginosa different antipathogenic compounds against gram-negative bacteria in general and
Quorum sensing inhibition against selected P. aeruginosa strains in particular. Several strategies for quorum
quenching have recently been deployed and recommended. The first approach is the
use of quorum quenching enzymes that target a broad range of AHLs. Quorum
quenching enzymes such as lactonase and acylase are able to inactivate a wide
range of AHLs. The second approach involves the use of different herbal extracts as
quorum quenching compounds against bacterial virulence. The third approach
combines the use of quorum quenching along with other supplemental treatments,
such as antibiotics, to obtain a synergistic effect in which the quorum quenching
compounds deliver the primary offensive capability to reduce bacterial capacity for
pathogenicity and increase the susceptibility of bacteria to antibiotic treatment. The
convergent approaches are discussed here to elaborate on how new as well as
previously available natural compounds such as active antipathogenic compounds
from garlic and other naturally occurring herbal sources can be utilized in novel
ways with the help of combinatorial chemistry to meet the challenges of increasing
threats from newly emergent and potent drug resistant microbes to treat
compromised individuals particularly with low immunity thresholds.

©2014 PVJ. All rights reserved

To Cite This Article: Hira Hameed and Saiyed I Ahmed, 2014. The role of chemical and herbal antipathogenic
compounds in the prevention of quorum sensing-dependent pathogenicity of Pseudomonas aeruginosa - A review.
Pak Vet J, 34(4): 426-431.

Quorum sensing: Bacterial growth, virulence or peptide signals are recognized by either membrane
pathogenic ability primarily depends on the ability of associated histidine kinase or cytoplasmic receptors
bacteria for cell-to-cell communication through a variety (Thoendel et al., 2011). Another type of auto inducer AI-2
of signal molecules. This type of communication among has also been identified, their chemical nature is still
or between bacteria is referred to as Quorum sensing (QS) unknown but they initiate QS both in Gram-negative and
(Rumbaugh et al., 2012). The molecules (auto inducers) Gram-positive bacteria (Xavier and Bassler, 2003;
used in signaling process in Gram positive and Gram- Galloway et al., 2011). Some of the auto inducers are
negative bacteria are different and distinct (Galloway et shared between prokaryotes and eukaryotes. It is
al., 2011). Biofilm formation and sporulation in Gram- hypothesized that cross kingdom communication also
positive organisms e.g. Bacillus subtilis has recently been exists and is more prevalent than had been previously
discussed thoroughly in a recent article by Liaqat et al. assumed (Iyer et al., 2004). For example, we know that
(2013). Gram-negative bacteria utilize N-acylated-L- QS is functional between prokaryotes but it can also exist
homoserine lactones (AHLs) which are produced by LuxI- between prokaryotes and eukaryotes. In eukaryotes, most
type synthase enzymes and bind to cytoplasmic LuxR of the enzymes, which help in communication, are
receptors to exert a regulatory output and Gram positive homologous to such structures, which help in quorum
bacteria use cyclic peptides as an auto inducer. The sensing in prokaryotes. These enzymes are present in

426
 427 Pak Vet J, 2014, 34(4): 426-431.

prokaryotes but absent in eukaryotes including plants, so oxodoecanoyl)-L-homserine lactone (3O-C12- HSL),
prokaryotes share these enzymes (e.g. which can bind to receptor Las R. This complex controls
Phenylethanolamine N-methyltransferase, glutamate the transcription of genes for several virulence factors,
decarboxylase, histidine decarboxylase, etc) with including alkaline protease, toxin A and elastases
eukaryotes and help them in quorum sensing (Iyer et al., (Schuster et al., 2003; Duan and Surcttc, 2007). The
2004). second type of QS system is named rhlI/R, where RhlI
synthase directs the production of N-butyryl-L-
Quorum sensing inhibition (QSI)/quorum quenching: homoserine lactone (C4-HSL) binding to receptor Rhl R
The cure or treatment of conventional infectious diseases (Bottomley et al., 2007). The complex so formed i.e. C4-
is based primarily on the use of antibiotics that aim to kill HSL-RhIR activates transcription of several genes
or inhibit bacterial growth (Sharon et al., 2009). The including rhl AB operon that encodes for the enzyme
major problem with this approach is the frequent responsible for rhamnolipid synthesis which are
development of antibiotic resistant strains of microbes intricately involved in biofilm formation.
under attack. For example, one prime strategy of P. aeruginosa also uses a third signal, Pseudomonas
resistance that P. aeruginosa utilizes is the development quinolone signal (PQS) and the PqsR receptor protein
of biofilm mode of growth. Through the use of this (Dubern and Diggle, 2008). This QS signal is responsible
strategy Pseudomonas effectively evades the action of for the expression of many virulence factors in P.
antibiotics since biofilms prevent effective concentrations aeruginosa (Schuster et al., 2003; Bottomley et al., 2007;
of antibiotics to penetrate to arrest and prevent the further Bredenbruch et al., 2006).
development of such opportunistic pathogens (Rasmussen
and Michael, 2006). The emergence of antibiotic resistant Quorum quenching against AHL mediated QS
strains of P. aeruginosa demands new approaches for 1) Quorum quenching enzymes: QSI or quorum
combating infections (Kaufmann et al., 2008). quenching in P. aeruginosa or gram-negative bacteria in
Accordingly, the use of selected signal molecules or cell- general can be interfered with in several ways. Since we
to-cell communication disrupting drugs (that will arrest know that in P. aeruginosa or in Gram-negative bacteria
the ability of invading microbes to launch their virulence quorum sensing is AHL based, so it can be blocked by
mechanisms through activation of responsible genes) can inhibition of AHL biosynthesis involved enzymes of acyl
potentially prove to be one of the most effective chain (acyl-acyl carrier protein) (ACP) and S-
strategies. Although, we will focus our attention here adenosylmethionine synthase (Parveen and Cornell,
primarily on P. aeruginosa, a Gram-negative bacterium, it 2011), as well as LuxI homolog proteins. For example,
behooves to remind the reader that this strategy can be various analogs of SAM (S-adenosyle methionine), such
equally effective against a variety of Gram-positive as S-adenosylhomocysteine, S-adenosylcysteine, and
bacteria. Compounds capable of such a type of sinefungin, have been demonstrated to be potent inhibitors
interference have been termed antipathogenic drugs and of AHL synthesis catalyzed by the P. aeruginosa RhlI
this phenomenon is also called quorum sensing inhibition protein (Pechere, 2001).
(QSI) or quorum quenching (Rasmussen and Michael, Second way in which quorum quenching can be
2006; Kalia and Purohit, 2011). Actually there are three exercised is through destruction of the QS signaling
main strategies for accomplishing quorum quenching molecules. In this way signal is not accumulated in the
either by targeting signal generation inhibition or by environment and is unable to initiate and express QS
inhibition of signal dissemination or signal receptor phenomena. Two enzymes that play a significant part in
inhibition (Dong et al., 2007). degradation of AHL have been discovered: i.e., AHL
lactonase and AHL acylase (Dong et al., 2007).For
Pseudomonas aeruginosa and its pathogenicity: P. example Bacillus spp. which is a Gram-positive
aeruginosa is an opportunistic pathogen of humans, bacterium, inhibits quorum sensing in Gram-negative or
animals as well as of plants and the most common gram- AHL autoinducer producing bacteria by lactonase
negative bacterium found in nosocomial infections of enzymes (A ii A) which cleave acyl moiety from lactone
urinary tract, bloodstream, pneumonia, and burn wound. It rings of AHL and utimately inactivate AHL. However, in
is also known for its connection with chronic infections of this mode it only acts as quorum quencher for AHL auto
the respiratory tract diseases including cystic fibrosis, inducer producing bacteria and its own communication
diffuse panbronchiolitis, and bronchiectasia (Bjarnsholt threshold remains uninterrupted (Dong et al., 2000; 2001).
and Givskov, 2007). Its survival and pathogenicity Similarly, human paraoxonase (PON2) enzymes are
depends on the production of lytic enzymes like protease, lactonase in nature so they also inhibit QS by targeting the
elastase, pyocynanin pigment, exopolysaccharide (EPS), signal transmission (Draganov et al., 2005; Ozer et al.,
and swarming motility (Adonizio et al., 2008; Vu et al., 2005). From other bacteria as diverse as Agrobacterium
2009). tumefaciens, Erwiniacarotovora, and Xanthomonas spp.
there are reports of autoinducer degradation activities
Quorum sensing in Pseudomonas aeruginosa: It has (Haudecoeur et al., 2009). Similarly, many other bacteria
been found that P. aeruginosa uses at least two QS produce AHL acylase and act as a quorum quencher by
systems for the formation of biofilm and other virulence targeting AHL molecules. They degrade the amide bonds
expression factors (Duan and Surcttc, 2007). The first QS resulting in the yield of homoserine lactone and fatty acid.
system of P. aeruginosa uses the LasI/R and the By this mechanism the AHL ring becomes open, which
concerned genes are LuxI/R homologues. In the LasI/R can serve as a ready source of energy and nitrogen
system, LasI synthase directs the synthesis of N-(3- compounds. As a further example Variovorax paradoxus
 428 Pak Vet J, 2014, 34(4): 426-431.

and Ralstonia specie XJ12Bendeavor toopen AHL ringsin CV026 and concluded that gorgonian extracts possessed
order to use products of AHL as carbon and nitrogen significant QS inhibitory activities on long chain AHL
sources (Leadbetter and Greenberg, 2000; Lin et al., from P. aeruginosa PAO1
2003;Nishino and Spain, 2006). In conclusion, lactonases Basavaraj et al. (2008) reported that natural fruit
and acylases are quite efficient quorum-quenching juices like grapefruit are known to inhibit biofilm
enzymes which can be utilized as effective antivirulence formation in Escherichia coli O157:H7, Staphylococcus
or antipathogenic tools against P. aeruginosa or other aureus, Salmonella and P. aeruginosa by acting on QS
Gram negative bacteria because of their ability to mechanisms of these bacteria. They concluded that
inactivate signaling molecules without interfering with the particularly furocoumarins from grapefruit possess such
enzymatic mechanisms inside the bacterial cells, thereby inhibitory capabilities on a number of bacterial species.
reducing the selective pressure exerted by the use of Dietary phytochemicals are secondary metabolites in
antibiotics. plants. Vattem et al. (2007) have tested some common
Finally, the third mode of quorum quenching in phyto chemicals from dietary fruit, herb and spice extracts
bacteria can be achieved by the inhibition of LuxR in model bioassay test systems. The effect of the
homolog proteins (Qs receptors) (Koch et al., 2005; Chen substances as antipathogenic drugs at sub-lethal
et al., 2011). For example, synthetic halogenated concentrations (SLCs) were investigated and resulted in
furanones from Delisea pulchra inhibit AHL-dependent the conclusion that indeed such compounds possessed
quorum sensing by displacing the AHL signal from its inhibitory QS related functions that were effective on
reporter protein (Manefield et al., 1999). Furanones from different bacterial properties like swarming motility of
marine algae Delisea pulchra do not act as quorum pathogens Escherichia coliO157:H7and P. aeruginosa,
quenching compounds against P. aeruginosa (de Nys et violaceum production in Chromobacterium violaceum o26
al., 1993) but synthetic furanones have demonstrated good (CVo26). Almost 200,000 compounds have been screened
efficacy (Rasmussen and Givskov, 2006). On the other which are potential inhibitors of LasR-dependent gene
hand a chemical compound, Iberin from horseradish expression and the two best inhibitors among these are
inhibits QS in P. aeruginosa by acting on RhIR receptors. tetrazole and V-06-018, with phenyl ring that normally
These receptors are used in the second type of QS system binds to Las R. Müh et al. (2006) observed that both of
deployed by P. aeruginosa (Jakobsen et al., 2012). these compounds inhibited the production of two QS
dependent virulence factors, elastase and pyocyanin in P.
2) Quorum quenching pressure exerted by herbal aeruginosa.
extracts: Many natural food products, herbs and spices Many other plants produce compounds which have
possess quorum sensing inhibitory properties for example, good QS inhibitory effects as an example, carrot, soya
garlic, carrot, and chamomile (Fulghesu et al., 2007). bean, water lilly, tomatoes pea seedlings, bean sprouts,
Among these, garlic (Allium sativum) is renowned for its vanilla and similar natural compound scan be very
antifungal, anticancerous, antiviral, antiprotozoal and effective QS inhibitory agents (Rasch et al., 2005; Choo et
antimicrobial activities (Block, 2010). It was al.,2006; Niu et al., 2006; Jaramillo et al., 2012). Most of
demonstrated that the antimicrobial activities related to these plant extracts exert a strong antagonistic effect on
the presence of growth inhibitory compounds, such as LuxR based QS. Due to the quorum quenching ability of
allicin, which is the active ingredient in garlic (Ankri and these plants, they have been used in food and flavor
Mirelman, 2001). Later on it was reported that ajoene industry as a preservative and to delay the onset of food
from garlic are naturally occurring substances which act spoilage (Rasmussen et al., 2005; Blana, 2011).The
as quorum quenching compound active against P. commonly used cuminum (Cuminum cyminum) and its
aeruginosa. Recently tested mouse model studies of secondary metabolite, methyl eugenol has been used
pulmonary infection have shown that ajoene elicited against Gram-negative bacterial pathogens such asP.
significant clearance of P. aeruginosa in these studies aeruginosa and it was found that it promoted the
(Jakobsen et al., 2012). Ajoene is a sulfur-containing loosening of biofilm architecture and strongly inhibited in
compound, which is produced when garlic is crushed. vitro biofilm formation of this organism (Packiavathy et
Michael and his team found that ajoene from garlic acts as al., 2011). Garlic and other similar spices in daily culinary
a quorum quencher for almost 11 virulence genes that are use as additives such as ginger and turmeric have been
responsible for P. aeruginosa infections (Michael, 2012). reported to possess QSI properties (Vattem et al., 2007).
Gorgonian corals are naturally occurring invertebrates, Similarly, several other commonly used substances like
which are found in coral reefs worldwide in marineeco essential oils of cinnamon (Niu et al., 2006) and clove
system (Bayer, 1961). Laura et al. (2012) tested different (Khan et al., 2009) can also act as potent QSI compounds
non-marine human pathogenic Gram-positive and Gram- against Gram-negative or AHL mediated QS. Several
negative bacteria as well as a variety of marine bacteria natural compounds have been shown to possess QSI
against the antimicrobial and quorum sensing inhibitory properties, like edible fruit (grape fruit), as well as marine
activities of gorgonian extracts. They found that among sponges and seaweeds (Skindersoe et al., 2008; Musthafa
the non-marine human pathogenic bacteria, P. aeruginosa et al., 2010) and even some bacteria themselves exhibit
PAO1, Bacillus subtilis, Vancomycin resistant QSI activities (Thenmozhi et al., 2009; Nithya et al.,
enterococcus, methicillin sensitive staphylococcus and 2010). Extracts from edible plants were tested as QS
Escherichia coli were sensitive to gorgonian extracts. inhibitors for examples, Melicope lunu-ankenda which is
They proceeded to examine the quorum sensing inhibitory a Malay garden salad, has been found by Tan et al. (2012)
effects of long chain AHL from P. aeruginosa PAO1 and to inhibit QS dependent virulence determinants of human
short chain AHL from Chromobacterium violaceum pathogen P. aeruginosa PAO1,s pyocyanin and swarming
 429 Pak Vet J, 2014, 34(4): 426-431.

motility. These plant extracts also inhibited other Gram- Patulin was found to enhance biofilm susceptibility to
negative bacterial virulence like that of Chromobacterium tobramycin treatment and patulin or penicillic acid also
violaceum CV026, violacein production and rendered the P. aeruginosa susceptible to
bioluminescence expression in E. coli [pSB401] by polymorphonuclear (PMLN) cells effect.
hindering response of their QS signal N-hexanoyl
homoserine lactone. Other benefits of quorum quenching: Bacterial
enzymes, which have been reported to be regulated by
3) Synergistic effect of combinatorial therapy with QS, for example different microbial extracellular enzymes
antimicrobial agents and herbal extracts enhances such as Pectate lyase, pectin lyase, polygalactouronase,
quorum quenching effects: Given the emergence and cellulase, lipases, chitinase, nuclease and protease have
increasing occurrence of multidrug resistance among a been known to cause food spoilage. As these enzymes
variety of pathogenic bacteria, the development of novel play a part in food spoilage, by inhibiting the regulatory
therapies for the treatment of bacterial infections, such as system of these enzymes by using various preservatives
those based on quorum quenching would be of huge with duel QSI properties, food spoilage could be delayed
clinical significance. Selective disruption of quorum or entirely prevented (Pirhonen et al., 1993; Rasmussen et
sensing should attenuate pathogenicity without imposing al., 2005; Van et al., 2006; Van et al., 2007).
the level of selective pressure associated with antibacterial Anti pathogenic drugs whose mode of action is
treatment (Defoirdt et al., 2010; Maeda et al., 2012). primarily QSI based mainly target the QS activities of
In most of pathogenic bacteria and especially in the bacteria and hence prevent the expression of bacterial
case of P. aeruginosa biofilm formation is critical QS virulence genes or stress survival genes but do not kill the
regulated phenomena. Biofilm production causes many pathogen itself. Accordingly, by using this mode of action
problems such as surgical instrument associated infections of anti pathogenic drugs, prevalence of the development
(nosocomial infections) and catheter-related bloodstream of antibiotic resistant strains can be avoided or minimized
infections (Donlan, 2001; Taylor and Webster, 2011). If (Tan et al., 2012).
QS could be controlled or disrupted then the formation of Food borne pathogens cause great economic losses to
biofilms could also be avoided or minimized but the extent of about 5-6 billion euros each year in Europe
sometimes with the disruption of QS in P. aeruginosa, alone and the pathogens that are primarily involved as
biofilm formation is not entirely prevented. However the
causative agents are Listeria monocytogenes, Salmonella,
simultaneous use of QSI compounds could make the
Escherichia coli, Pseudomonas spp. and Entero-
infection more susceptible to antibiotic compounds
bacteriaceae (Koutsoumanis 2009; Scallan et al., 2011).
(Estrela and Abraham, 2010; Brackman et al., 2011).
Rhamno lipids that form as a result of QS, provide the
Amide bond
bacteria such an environment in order to escape from the degradation 3. Signal
inhibition AHL
Acyl moiety
cleave

host immune defense system. The quorum quenching

mechanisms render the bacteria more sensitive to PMNLs AHL Lactonase
AHL AHL
by depressing the strength of biofilm or rhamno lipid Acylase

formation (Bjarnsholt et al., 2005).

2. Signal receptor
Christensen et al. (2012) reported synergistic effects inhibition

of antibiotic and herbal extract against P. aeruginosa and

1. Sig hibition

found much more pronounced results. e.g. ajoene from AHL

nal ge
in

SAM
garlic combined with the antibiotic tobramycin killed over LuxI LuxR
nerati

`
90% of bacteria which were involved in biofilm formation
on

Pseudomonas
instead of tobramycin alone which killed less than 10%. Acyl-ACP Lux R
virulence gene
expression

Michael (2012) subsequently reported that combinatorial

therapy of garlic with antibiotic decreased the dose of
garlic used. The dose of garlic, which had given good
results against P. aeruginosa in adult human, was 50 Fig. 1: Three pathways of QSI in Pseudomonas aeruginosa AHL mediated
QS
bulbs of garlic for several days but that also generated a
multitude of unwanted side effects. However, when garlic
was given in combination with antibiotic (tobramycin), Conclusion: As frequent or indiscriminate use of
their synergistic effect permitted the reduction in very antibiotics against bacterial infections leads to increasing
high doses of garlic. development of resistant strains which is becoming a
Rasmussen et al. (2005) studied the QSI properties of global threat to public health. Accordingly the use of
fungi and identified two compounds from fungi, which novel therapeutic agents are becoming of ever-greater
have QSI activity on P. aeruginosa biofilm. These importance. Towards this end the target of the scientist is
compounds not only attenuate P. aeruginosa but make P. to attenuate virulence without causing selection pressure.
aeruginosa biofilms highly susceptible to treatment with QS is a key regulatory system that is responsible for the
conventional antibiotics like selective P. aeruginosa expression of virulence determinants, thus by under-
antibiotic tobramycin. Most of the secondary metabolites standing the potential of quorum sensing as an effective
isolated from filamentous fungi, which are already used target against bacteria, new forms of anti pathogenic drugs
clinically as antimicrobial drugs, also act as QSI at can be developed and promoted. This effort can lead to
sublethal doses. Patulin and penicillic acid have been the development of novel therapeutics that can prevent
identified as being biologically active QSI compounds. and control the spread of microbial infections.
 430 Pak Vet J, 2014, 34(4): 426-431.

QSI compounds are naturally found in many of our Dong YH, LH Wang, JL Xu, HB Zhang, XF Zhang and LH Zhang, 2001.
Quenching quorum sensing dependent bacterial infection by an N-
daily consumed foods (plants, herbs, vegetables, spices acyl homoserine lactonase. Nature, 411: 813-817.
and these selective studies of these products and their Dong YH, LY Wang and LH Zhang, 2007. Quorum quenching microbial
active ingredients which result in specific beneficial infections: mechanisms and implications. Philos Trans R Soc Lond
effects including control of selected pathogens would B Biol Sci, 362: 1201-1211.
Donlan RM, 2001. Biofilms and device associated infections. Emerg
render the dawn of a new age in pharmacotherapy. We are Infect Dis, 7: 277-281.
currently embarked on studies of active ingredients from Draganov DI, JF Teiber, A Speelman, Y Osawa, R sunahara and BN La
Moringa (Moringa oleifera), Neem (Azadirachta indica), Du, 2005. Human paraoxonases (PON1, PON2, and PON3) are
ginger (Zingiber officinale), onion (Allium cepa) and a lactonases with overlapping and distinct substrate specificities. J
Lipid Res, 46: 1239-1247.
variety of other herbs and spices as sources of QSI Dubern JF and SP Diggle, 2008. Quorum sensing by 2-alkyl-4-quinolones
compounds for testing against the pathogenicity of P. in Pseudomonas aeruginosa and other bacterial species. Mol Biosyst,
aeruginosa. Our goal is to shed additional light and 4: 882-888.
attempt to elucidate intricate mechanisms by which QSI Estrela AB and WR Abraham, 2010. Combining biofilm- controlling
compounds and antibiotics as a promising new way to control
compounds from such sources exercise their beneficial biofilm infections. Pharmaceuticals, 3: 1374-1393.
effects on human pathophysiology. Fulghesu L, C Giallorenzo and D Savoia, 2007. Evaluation of different
compounds quorum sensing inhibitors in Pseudomonas aeruginosa. J
REFERENCES Chemother, 19: 388-391.
Galloway WR, JT Hodgkinson, SD Bowden, M Welch, and DR Spring,
2011. Quorum sensing in Gram-negative bacteria: small molecule
Adonizio A, KF Kong and K Mathee, 2008. Inhibition of quorum
modulation of AHL and AI-2 quorum sensing pathways. Chem
sensing-controlled virulence factor production in Pseudomonas
Rev, 111: 28-67.
aeruginosa by South Florida plant extracts. Antimicrob Agents
Givskov M, 2012. Beyond nutrition: health-promoting foods by quorum
Chemother, 52: 198-203.
sensing inhibition. Future Microbiol, 7: 1025-1028.
Ankri S and D Mirelman, 1999. Antimicrobial properties of allicin from
Haudecoeur E, M Tannieres, A Cirou, A Raffoux, Y Dessaux and D
garlic. Microbes Infec, 1: 125-129.
Faure, 2009. Different regulation and roles of lactonases AiiB and
Bayer FM, 1961. The shallow water octocorallia of the West Indian
AttM IN Agrobacterium tumefaciens C58. Mol Plant Microbe
region: A manual for marine biologists; Martinus Nijhoff: The
Interact, 22: 529-537.
Hague, The Netherland, pp: 55.
Iyer LM, L Aravind, SL Coon, DC Klein and EV Koonin, 2004. Evolution
Bjarnsholt T and M Givskov, 2007. Quorum-sensing blockade as a
of cell-cell signaling in animals: did late horizontal gene transfer
strategy for enhancing host defences against bacterial pathogens. from bacteria have a role? Trends Genet, 20: 292-299.
Philos Trans R Soc Lond B Biol Sci, 362: 1213-1222. Jakobsen TH, M van Gennip, RK Phipps, MS Shanmugham, LD
Bjarnsholt T, PØ Jensen, M Burmølle, M Hentzer, JA Haagensen, HP Christensen, M Alhede, ME Skindersoe, TB Rasmussen, K
Hougen, H Calum, KG Madsen, C Moser, S Molin, N Høiby and Friedrich, F Uthe, PØ Jensen, C Moser, KF Nielsen, L Eberl, TO
M Givskov, 2005. Pseudomonas aeruginosa tolerance to tobramycin, Larsen, D Tanner, N Høiby, T Bjarnsholt and M Givskov, 2012.
hydrogen peroxide and polymorphonuclear leukocytes is quorum- Ajoene, a sulfur rich molecule from garlic, inhibits genes
sensing dependent. Microbiology, 151: 373-383. controlled by quorum sensing. Antimicrob Agents Chemother, 56:
Blana VA, 2011. Quorum sensing: understanding the role of bacteria in 2314-2325.
meat spoilage. PhD Thesis. Cranfield University, Cranfield, United Jakobsen TH, SK Bragason, RK Phipps, LD Christensen, M van Gennip,
Kingdom. M Alhede, M Skindersoe, TO Larsen, N Høiby, T Bjarnsholt and M
Block E, 2010. Garlic and other alliums. The Lore and the Science Givskov, 2012. Food as a source for quorum sensing inhibitors:
Publisher, RSC Cambridge, UK. iberin from horseradish revealed as a quorum sensing inhibitor of
Bottomley MJ, E Muraglia, R Bazzo and A Carfi, 2007. Molecular insights Pseudomonas aeruginosa. Appl Environ Microbiol, 78: 2410-2421.
into quorum sensing in the human pathogen Pseudomonas Jaramillo-Colorado B, J Olivero-Verbel, EE Stashenko, I Wagner-Döbler
aeruginosa from the structure of the virulence regulator LasR and B Kunze, 2012. Anti-quorum sensing activity of essential oils
bound to its autoinducer. J Biol Chem, 282: 13592-13600. from Colombian plants. Nat Prod Res, 26: 1075-1086.
Brackman G,P Cos, L Maes, HJ Nelis and T Coenyel, 2011. Quorum Kalia VC and HJ Purohit, 2011. Quenching the quorum sensing system:
sensing inhibitors increase the susceptibility of bacterial biofilms to potential antibacterial drug targets. Crit Rev Microbiol, 37: 121-
antibiotics in vitro and in vivo. Antimicrob Agents Chemother, 55: 140.
2655-2661. KaufmannGF, J Park and KD Janda, 2008. Bacterial quorum sensing: a
Bredenbruch F, R Geffers, M Nimtz, J Buer and S Häussler, 2006. The new target for anti-infective immunotherapy. Expert Opin Biol
Pseudomonas aeruginosa quinolone signal (PQS) has an iron- Ther, 6: 719-724.
chelating activity. Environ Microbiol, 8: 1318-1329. Khan MS, M Zahin, S Hasan, FM Hussain and I Ahmad, 2009. Inhibition
Chen G, LR Swern, DL Swern, DL Stauff, CT O’Loughlin, PD Jeffrey, BL of quorum sensing regulated bacterial functions by plant essential
Bassler and FM Hughson, 2011. A strategy for antagonizing oils with special reference to clove oil. Lett Appl Microbiol, 49:
quorum sensing. Mol Cell, 42: 199-209. 354-359.
Choo JH, Y Rukayadi and JK Hwang, 2006. Inhibition of bacterial Koch B, T Liljefors, T Persson, J Nielsen, S Kjelleberg and M Givskov,
quorum sensing by vanilla extract. Lett Appl Microbiol, 42: 637- 2005. The LuxR receptor: The sites of interaction with Quorum-
641. sensing signals and inhibitors. Microbiol, 151: 3589-3602.
Christensen LD, GM Van, TH Jakobsen, M Alhede, HP Hougen, N Koutsoumanis K, 2009. Modeling food spoilage in microbial risk
Høiby, T Bjarnsholt and M Givskov, 2012. Synergistic antibacterial assessment. J Food Prot, 72: 425-427.
efficacy of early combination treatment with tobramycin and Laura RH, SM Smith, KR Downum and LD Mydlarz, 2012. Microbial
quorum-sensing inhibitors against Pseudomonas aeruginosa in an regulation in gorgonian corals. Mar Drugs, 10: 1225-1243.
intraperitoneal foreign-body infection mouse model. J Antimicrob Leadbetter JR, and EP Greenberg, 2000. Metaboolism of
Chemother, 65: 1198-1206. acylhomoserine lactone quorum-sensing signals by Variovorax
de Nys R, AD Wright, GM König and O Sticher, 1993. New paradoxus. J Bacteriol, 182: 6921-6926.
halogenated furanones from the marine alga Delisea pulchra (cf. Liaqat I, SI Ahmed and N Jahan, 2013. Biofilm formation and sporulation
fimbriata). Tetrahedron, 49: 11213-11220. in Bacillus subtilis. Int J Microbiol Res Rev, 1: 61-67.
Defoirdt T, N Boom and P Bossier, 2010. Can bacteria evolve Lin YH, JL Xu, J Hu, LH Wang, SL Ong, JR Leadbetter and LH Zhang,
resistance to quorum sensing disruption? PLoS Pathog, 6: 2003. Acyl-homoserine lactone acylase from Ralstonia strain XJ12B
e1000989. represents a novel and potent class of quorum quenching
Dong YH, JL Xu, XZ Li and LH Zhang, 2000. AiiA, an enzyme that enzymes. Mol Microbiol, 47: 849-860.
inactivates the acylhomoserine lactone quorum-sensing signal and Maeda T, R Garcia-Contreras R, M Pu, L Sheng, LR Garcia, M Tomas
attenuates the virulence of Eriwinia carotvora. Proc Natl Acad Sci and TK Wood, 2012. Quorum quenching quandary: resistance to
USA, 97: 3526-3531. antivirulence compounds. ISME J, 6: 493-501.
 431 Pak Vet J, 2014, 34(4): 426-431.

Manefield M, R de Nys, N Kumar, R Read, M Givskov, P Steinberg and S Rasmussen TB, ME Skindersoe, T Bjarnsholt, RK Phipps, KB
Kjelleberg, 1999. Evidence that halogenated Furanones from Christensen, PO Jensen, JB Andersen, B Koch, TO Larsen, M
Delisea pulchra inhibit acylated homoserine lactone (AHL)- Hentzer, L Eberl, N Hoiby and M Givskov, 2005. Identity and
mediated gene expression by displacing the AHL signal from its effects of quorum-sensing inhibitors produced by Penicillium
receptor protein. Microbiology, 145: 283-291. species. J Microbiol, 151: 1325-1340.
Müh U, BJ Hare, BA Duerkop, M Schuster, B Hanzelka, R Heim, ER Rasmussen TB, T Bjarnsholt, ME Skindersoe, M Hentzer, P
Olson and EP Greenberg, 2006. A structurally unrelated mimic of Kristoffersen, M Köte, J Nielsen, L Eberl and M Givskov, 2005.
a Pseudomonas aeruginosa acyl-homoserine lactone quorum-sensing Screening for quorum-sensing inhibitors (QSI) by use of a novel
signal. Proc Natl Acad Sci USA, 45: 16948 -16952. genetic system, the QSI selector. J Bacteriol, 187: 1799-1814.
Musthafa KS, AV Ravi, A Annapoorani, IS Packiavathy and SK Pandian, Rasmussen, TB and G Michael, 2006.Quorum-sensing inhibitors as anti-
2010. Evaluation of anti-quorum sensing activity of edible plants pathogenic drugs. Int J Med Microbiol, 296:149-161.
and fruits through inhibition of the N-acyl-homoserine lactone Scallan E, RM Hoekstra, FJ Angulo, RV Tauxe, MA Widdowson, SL Roy,
system in Chromobacterium violaceum and Pseudomonas aeruginosa. JL Jones and PM Griffin, 2011. Foodborne illness acquired in the
Chemotherapy, 56: 333-339. United States-major pathogens. Emerg Infect Dis, 17: 7-15.
Nishino SF and JC Spain, 2006. Biodegradation of 3-nitrotyrosine by Schuster M, CP Lostroh, T Ogi and EP Greenberg, 2003. Identification,
Burkholderia sp. Strain JS165 and Variovorax paradoxus JS171. Appl timing and signal specificity of Pseudomonas aeruginosa quorum-
Environ Microbiol, 72: 1040-1044. controlled genes: a transtriptome analysis. J Bacteriol, 185: 2066-
Nithya C, C Aravindraja and SK Pandian, 2010. Bacillus pumilus of Palk 2079.
Bay origin inhibits quorum-sensing mediated virulence factors in Skindersoe ME, P Ettinger-Epstein, TB Rasmussen, T Bjansholt, R de
gram-negative bacteria. Res Microbiol, 161: 293-304. Nys and M Givskov, 2008. Quorum sensing antagonism from
Niu C, S Afre and ES Gillbert, 2006. Subinhibitory Concentrations of marine organisms. Mar Biotechnol, 10: 56-63.
cinnamaldehyde interfere with quorum sensing. Lett Appl Tan LY, WF Yin and KG Chan, 2012. Silencing quorum sensing through
Microbiol, 43: 489-494. extracts of Melicope lunu-ankenda. Sensors, 12: 4339-4351.
Ozer EA, A Pezzulo, DM Shih, C Chun, C Furlong, AJ Lusis, EP Taylor E and TJ Webster, 2011. Reducing infections through
Greenberg and J Zabner, 2005. Human and marine paraxonase 1 nanotechnology and nanoparticles. Int J Nanomed, 6: 1463-1473.
are host modulators of Pseudomonas aeruginosa quorum sensing. Thenmozhi R, P Nithyanand, J Rathna and SK Pandian, 2009. Antibiofilm
FEMS Microbiol Lett, 253: 29-37. activity of coral-associated bacteria against different clinical M
Packiavathy IASV, P Agilandeswari, KS Musthafa, SK Pandian and AV serotypes of Streptococcus pyogenes. FEMS Immunol Med
Ravi, 2011 Antibiofilm and quorum sensing inhibitory potential of Microbiol, 57: 284-294.
Cuminum cyminum and its secondary metabolite methyl eugenol Thoendel M, JS Kavanaugh, CE Flack, and AR Horswill, 2011. Peptide
against Gram negative bacterial pathogens.Food Res Int, 45: 85-92. signaling in the staphylococci. Chem Rev, 111: 117-151.
Parveen N and KA Cornell, 2011. Methylthioadenosine/S- Van HR, P Moons, A Aertsen, A Jansen, K Vanoirbeek, M Daykin, P
adenosylhomocysteine nucleosidase, a critical enzyme for bacterial Williams and CW Michiels, 2007. Characterization of a luxI/luxR-
metabolism. Mol Microbiol, 79: 7-20. type quorum sensing system and N-acyl-homoserine lactone-
Pechere JC, 2001. Azithromycin reduces the production of virulence dependent regulation of exo-enzyme and antibacterial component
factors in Pseudomonas aeruginosa by inhibiting quorum sensing. Jpn production in Serratia plymuthica RVH1. Res Microbiol, 158: 150-158.
J Antibiotics, 54: 87-89. Van HR, P Moons, BM Hueso and CW Michiels, 2006. N-Acyl-L-
Pirhonen M, D Flego, R Heikinheimo and ET Palva, 1993. A small homoserine lactone quorum sensing controls butanediol
diffusible signal molecule is responsible for the global control of fermentation in Serratia plymuthica RVH1 and Serratia marcescens
virulence and exoenzyme production in the plant pathogen Erwinia MG1. J Bacteriol, 188: 4570-4572.
carotovora. EMBO J, 12: 2467-2476. Vattem DA, K Mihalik, SH Crixelland and RJ Mc-Lean, 2007. Dietary
Rumbaugh KP, U Trivedi, C Watters, MN Burton-Chellew, SP Diggle phytochemicals as quorum sensing inhibitors. Fitoterapia, 78: 302-
and SA West, 2012. Kin selection, quorum sensing and virulence 310.
in pathogenic bacteria. Proc Biol Sci, 279: 3584-3588. Vu B, M Chen, RJ Crawford and EP Ivanova, 2009. Bacterial
Rasch M, JB Andersen, KF Nielsen, LR Flodgaard, H Christensen, M extracellular polysaccharides involved in biofilm formation. Mol,
Givskov and L Gram, 2005. Involvement of bacterial quorum- 14: 2535-2554.
sensing signals in spoilage of bean sprouts. Appl Environ Microbiol, Xavier KB and BL Bassler, 2003. LuxS quorum sensing: more than just a
71: 3321-3330. numbers game. Curr Opin Microbiol, 6: 191-197.