•Overview of cell-to-cell communication
or quorum sensing
Prokaryotic cell
Communication
Iman Rusmana
Department of Biology
Introduction
Quorum sensing is cell to cell signaling mechanism that
enables the bacteria to collectively control gene expression.
This type of bacterial communication is achieved only at
higher cell densities.
Bacteria release various types of molecules called as
autoinducers in the extracellular medium, these molecules are
mediators of quorum sensing.
Quorum Sensing
•
Tomasz (1965)
–
Gram-positive
Streptococcus pneumoniae
produce a
“
competence factor
”
that controlled factors for
uptake of DNA (natural transformation)
•
Nealson
et al.
(1970)
–
luminescence in the marine
Gram-negative bacterium
Vibrio fischeri
controlled by self-produced
chemical signal termed autoinducer
•
Eberhard
et al
. (1981) identified the
V. fischeri
autoinducer
signal to be
N
-3-oxo-hexanoyl-L-homoserine lactone
•
Engebrecht
et al.
(1983) cloned the genes for the signal
• Fuqua
et al
. (1994) introduced the term
“
quorum
sensing
”
to describe cell-cell signaling in bacteria
• Early 1990
’
s
–
homologs of LuxI were discovered in
different bacterial species
•
V. fischeri
LuxI-LuxR signaling system becomes the
paradigm for bacterial cell-cell communication
Symbiosis between
Quorum Sensing PubMed Citations
Year (2006. 03.15)
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TABLE
1
Organisms possessing LuxI/LuxR homologues: the regulatory
proteins, the HSL autoinducers, and the regulated functions
aLuxI/LuxR Target Genes and Organism Homologue(s) Autoinducer Identity Functions
Vibrio fischeri LuxI/LuxR N-(3-oxohexanoyl)- luxICDABE
(biolumin- HSL escence) (28, 31)
Aeromonas AhyI/AhyR N-butanoyl-HSL Serine protease and metal- hydrophila loprotease production
(154)
Aeromonas AsaI/AsaR N-butanoyl-HSL aspA (exoprotease) (155) salmonicida
Agrobacterium TraI/TraR N-(3-oxooctanoyl)- tra, trb (Ti plasmid
conju- tumefaciens HSL gal transfer) (124, 174)
Burkholderia CepI/CepR N-octanoyl-HSL Protease and siderophore
cepacia production (87)
Chromobacterium CviI/CviR N-hexanoyl-HSL Violacein pigment, hydro- violaceum gen cyanide, antibiotics,
exoproteases and
chitino- lytic enzymes (14, 96)
Enterobacter EagI/EagR N-(3-oxohexanoyl)- Unknown (156)
agglomerans HSL
Erwinia (a) ExpI/ExpR N-(3-oxohexanoyl)- (a) Exoenzyme synthesis,
carotovora (b) CarI/CarR HSL (72, 125) (b) Carbapenem antibiotic
synthesis (4)
Erwinia ExpI/ExpR N-(3-oxohexanoyl)- pecS (regulator of chrysanthemi HSL pectinase synthesis)
(103, 132)
Erwinia stewartii EsaI/EsaR N-(3-oxohexanoyl)- Capsular polysaccharide HSL biosynthesis, virulence
(10)
Escherichia coli ?/SdiA ? ftsQAZ (cell division), chromosome replication
(44, 144, 170)
Pseudomonas PhzI/PhzR N-hexanoyl-HSL phz (phenazine antibiotic
aereofaciens biosynthesis) (123, 171)
Pseudomonas (a) LasI/LasR (a) N-(3-oxodode- (a) lasA, lasB, aprA, toxA
aeruginosa canoyl)-HSL (exoprotease virulence factors), biofilm
forma- tion (19, 22 and references therein; 114) (b) RhlI/RhlR (b) N-butyryl-HSL (b) lasB, rhlAB
(rhamnoli-pid), rpoS
(stationary phase)
(22 and references therein; 82, 115)
Ralstonia SolI/SolR N-hexanoyl-HSL, Unknown (34) solanacearum N-octanoyl-HSL
Rhizobium etli RaiI/RaiR Multiple, unconfirmed Restriction of nodule
number (134)
Rhizobium (a) RhiI/RhiR (a) N-hexanoyl-HSL (a) rhiABC (rhizosphere leguminosarum genes) and stationary
phase (18, 51, 133) (b) CinI/CinR (b) N-(3-hydroxy-7- (b) Quorum sensing
cis-tetradecenoyl)- regulatory cascade
HSL (90)
Rhodobacter CerI/CerR 7,8-cis-N- Prevents bacterial
sphaeroides (tetradecanoyl)-HSL aggregation (130)
Salmonella ?/SdiA ? rck (resistance to typhimurium competence killing),
ORF on Salmonella
virulence plasmid (1)
Serratia SwrI/? N-butanoyl-HSL Swarmer cell differen- liquefaciens tiation, exoprotease
(30, 47)
Vibrio anguillarum VanI/VanR N-(3-oxodecanoyl)- Unknown (97) HSL
Yersinia YenI/YenR N-hexanoyl-HSL, Unknown (157) enterocolitica N
-(3-oxohexanoyl)- HSL
Yersinia (a) YpsI/YpsR (a) N-(3-oxohexanoyl)- Hierarchical quorum pseudotuberculosis HSL sensing cascade
(b) YtbI/YtbR (b) N-octanoyl-HSL regulating bacterial aggregation and
motility (3)
aMuch of the information in this table comes from (22) with permission.
•
Vast array of molecules are used as chemical
signals
–
enabling bacteria to talk to each other,
and in many cases, to be multilingual
Quorum Sensing
Gram-negative
bacteria
Gram-positive
bacteria
O N O O O N O O OH O N O O O N N O O N N O O OH N O OH O O OH Br H Br O O O O OH O O O R1 R3 R2
QS signals - Autoinducers
acyl homoserine lactones
N-butanoyl-L-homoserine lactone (BHL)N-(3-hydroxybutanoyl)- L-homoserine lactone (HBHL)
N-(3-oxohexanoyl)- L-homoserine lactone (OHHL)
diketopiperazines
cyclo(L-Pro-L-Tyr)
cyclo-(vAla-L-Val)
YSTCDFIM
S C O
ERGMT
ERGMT
Oligopeptides
Furanones
3-Hydroxypalmitic acid methyl ester (3OH PAME)
2-Heptyl-3-hydroxy-4-quinolone (PQS) butyrolactone
4-bromo-5-(bromomethylene)-3-(1 P -hydroxybutyl)-2(5H)-furanone
The three general classes of quorum-sensing systems
Modified oligopeptides Processin g and secreatio n S H K A R A T PADPClass
Autoinducer
Strain
O O R 1 H N O R 2
P. aeruginisa
V. fisheri
E. carotovora
A. tumefaciens
Y. enterocolitica
E. coli O157:H7
QS upregulates virulence gene expression
Quorum sensing controlled processes
Bioluminescence
Biofilm formation
Virulence gene expression
Sporulation
Competence
It occurs in various marine bacteria
such as
Vibrio harveyi
and
Vibrio fischeri.
Takes place at high cell density.
It iscompact mass of differentiated microbial cells, enclosed
in a matrix of polysaccharides. Biofilm resident bacteria
are antibiotic resistant. Quorum sensing is responsible for
development of thick layered biofilm.
QS upregulates spore-forming genes in
Bacillus subtilis
How quorum sensing works?
Signalling compounds, autoinducers
AI synthases (
luxI
gene products)
cell density indicators
- non-essential aa, acyl homoserine lactones
lactone ring part - binding to a receptor site
acyl chain tail – determining the species specificity
- oligopeptides
- diketopiperazines
- quinolone
- furanones
Recognition systems
LuxR
transcriptional regulator
specific binding sites for AHL and DNA (sensor/transducer)
Genetic basis
Cell density and quorum sensing
R gene I gene
R protein I protein
AHL diffuse out
R gene I gene
R protein I protein
AHL diffuse
out
+
AHL diffuse in
Cell
density
Time (min)
0
60
120
180
240
300
C
el
l d
e
n
s
it
y
(
O
D
66
0
n
m
)
0.01
0.1
1
B
io
lu
m
in
e
s
ce
n
ce
(
R
L
U
/m
l)
0.1
1
10
Cell density (OD660nm)
0.0
0.1
0.2
0.3
0.4
B
io
lu
m
in
es
ce
n
ce
/c
e
ll
(
R
L
U
/m
l/O
D
6
00
n
m
)
0
5
10
15
20
25
Nealson (1977) Arch. Microbiol. 112:73-79
•
In
V. fisheri
, bioluminsecence only occurs when
V.
fischeri
is at high cell density
Quorum Sensing
Quorum Sensing in
Pseudomonas aeruginosa
•
P. aeruginosa
uses a hierarchical quorum sensing
Quorum Sensing in Gram-Positive Bacteria
•
Gram-positive bacteria utilizes modified
oligopeptides as signaling molecules
–
secreted via
an ATP-binding cassette (ABC) transporter complex
•
Detectors for these signals are two-component
signal transduction systems
sensor kinase
- binding of autoinducer leads to
autophosphorylation at conserved
histidine residue
response regulator
Quorum sensing control of competence and sporulation in
Bacillus subtilis. B. subtilis
employs two processed peptide
autoinducers,
ComX (
gray circles) and
CSF
(white diamonds), to regulate the competence and sporulation processes.
Accumulation of the processed ComX peptide enables it to interact with the ComP sensor kinase. ComP
autophosphorylates on a histidine residue (H), and subsequently phosphate is transferred to an aspartate residue (D) on
the ComA response regulator.
Phospho-ComA
activates the transcription of
comS
. The ComS protein increases the
level of
ComK
protein (+) by inhibiting ComK proteolysis. ComK is a transcription factor that activates the
expression of genes required for development of the competent state.
The second peptide autoinducer, competence and sporulation factor (CSF), while accumulating extracellularly in a
density-dependent manner, has an intracellular role. CSF is transported into the cell via the Opp transporter (gray
protein complex).
At low internal concentrations CSF
inhibits the
ComA-specific phosphatase RapC
. Inhibition of RapC increases the
level of phospho-ComA, which leads to competence (dashed lines).
At high internal CSF concentrations
, CSF inhibits competence and promotes spore development (black lines).
Specifically, CSF inhibits ComS. CSF inhibition of ComS activity reduces transcription of competence genes,
promoting sporulation instead. Additionally, CSF inhibits the
RapB phosphatase
. The role of RapB is to
dephosphorylate the response regulator Spo0A.
Phospho-Spo0A
induces sporulation. Therefore, CSF inhibition of the
RapB phosphatase increases the phospho-Spo0A levels, and this leads to sporulation.
[Miller et al., 2001.
Annu. Rev. Microbiol. 55:165-199]
.
Hybrid quorum sensing circuit in
Vibrio harveyi
•
V. harveyi
–
marine bacterium, but unlike
V. fischeri
,
does not live in symbiotic associations with higher
organisms, but is free-living
•
Similar to
V. fischeri
, V
. harveyi
uses quorum sensing
to control bioluminescence
•
Unlike
V. fischeri
and other gram-negative bacteria,
V.
harveyi
has evolved a quorum sensing circuit that has
characteristics typical of both Gram-negative and
•
V. harveyi
uses acyl-HSL similar to other
Gram-negatives but signal detection and relay
apparatus consists of two-component proteins
similar to Gram-positives
•
V. harveyi
also responds to AI-2 that is designed
for interspecies communication
Hybrid quorum sensing circuit in
Vibrio harveyi
AI-1
AI-2
LuxN and LuxQ –
autophosphorylating kinases at low cell densities
Accumulation of autoinducers – LuxN and LuxQ phosphatases draining phosphate from LuxO via LuxU
Dephosphorylated LuxO is inactive
repressor X not transcribed
Quorum-sensing and the regulation of
bioluminescence in
V. harveyi
.
A: At low cell density,
in the absence of HBHL and AI-2,
LuxN and LuxQ autophosphorylate. A multistep
phosphorelay continues through the shared
phosphotransfer protein, LuxU, ultimately phosphorylating
the response regulator, LuxO. Phosphorylated LuxO, in
conjunction with
54
, is thought to indirectly repress
transcription of the genes required for bioluminescence
by activating the transcription of an unidentified negative
regulator (repressor X).
B: At high cell density, corresponding to a critical
concentration of signal molecules, LuxN and LuxQ/P sense
their cognate signals and switch from kinases to
phosphatases. Consequently, dephosphorylation of LuxO
results in its inactivation thereby preventing the
up-regulation of repressor X activity. Such de-repression
AI-2
Lux
P
H1
D1
H1
D1
LuxQ
LuxN
p
H2
D2
HTH
54LuxO
Repressor
LuxCDABE
IM OMH1
D1
H1
D1
p
H2
D2
HTHLuxO
LuxCDABE
LuxR
LuxS
LuxM
AI-1
Low Cell
density
High Cell
density
QS mechanisms in
V. harveyi
LuxU
LuxS and interspecies communication
•
LuxS homologs found in both Gram-negative and
Gram-positive bacteria; AI-2 production detected
in bacteria such as
E. coli
,
Salmonella
typhimurium
,
H. pylori
,
V. cholerae
,
S.aureus, B.
subtilis
using engineered
V. harveyi
biosensor
•
Biosynthetic pathway, chemical intermediates in
AI-2 production, and possibly AI-2 itself, are
identical in all AI-2 producing bacteria to date
–
reinforces the proposal of AI-2 as a
“
universal
”
'Bacterial esperanto' — a universal language?
The initial description of Vibrio fischeri quorum sensing was paralleled by a similar description in the related
luminescent marine bacterium Vibrio harveyi103. Before we had any mechanistic understanding of acyl-homoserine
lactone (acyl-HSL) signalling, it was shown that many other marine bacteria made something that signalled V. harveyi to induce its luminescence genes104.
It seemed that V. harveyi might measure the total bacterial load in its local environment rather than simply its own population size104.
There are, in fact, two integrated quorum-controlled circuits that govern the V. harveyi lux genes, either of which can induce luminescence independently43. The signal for one is the acyl-HSL 3-OH-C4-HSL105. The second
quorum-sensing system is based on a signal originally described as autoinducer-2 (AI-2), and it is this system that responds to interspecies bacterial signals106, 107. There is an increasing amount of evidence that bacteria other than V. harveyi
respond to AI-2-type signals and that, by analogy with V. harveyi, these microbes might also monitor the abundance of other AI-2-synthesizing bacteria in their local environment108.
A gene called luxS, which is conserved in a diverse range of bacteria, is responsible for the production of AI-2 by
Escherichia coli109. LuxS is an enzyme that can synthesize a molecule derived from S-ribosylhomocysteine, an
intermediate in methionine recycling110, 111. Despite this information and tremendous efforts, the true nature of the
AI-2 signal remained elusive. Only recently have Bonnie Bassler and colleagues identified the enigmatic signal,
associated with its receptor protein: receptor-bound AI-2 is a furanosyl borate diester112. Apparently, the sugar from
S-ribosylhomocysteine is cyclized and an atom of boron is incorporated to form the diester. Not only does this work provide at least one view of the interspecies signal, but it also suggests an unexpected role for elemental boron in the signalling pathway.
LuxS quorum sensing: more than just a
Infect Immun. 2000 Jun;68(6):3193-9.
Alignment of the deduced H.pylori LuxS sequence with deduced LuxS sequences from four other bacterial species. LuxS sequences from H.pylori 26695 (GenBank accession no. AE000532), S.aureus (preliminary sequence data obtained from The Institute for Genomic Research website at http://www.tigr.org/), B.subtilis (accession no. Z9919),
Genes and functions controlled by LuxS in bacteria
The molecular basis of bioluminescence regulation
The LuxI family of acyl HSL synthase proteins
A putative scheme for HHL synthesis, catalysed by LuxI. SAM binds to the active site on LuxI, and
the hexanoyl group is transferred from the appropriately charged ACP. The hexanoyl group forms
an amide bond with the amino group of SAM. 5 -Methylthioadenosine is released, and a
′
O
O
R
1
H
N
O
R
2
The quorum-sensing molecules. A–H: Some of the more common microbial acyl HSLs: (A)
N-butanoyl-L-homoserine lactone (BHL); (B) N-(3-hydroxybutanoyl)-L-homoserine lactone (HBHL); (C)
N-hexanoyl-L-homoserine lactone (HHL); (D) N-(3-oxohexanoyl)-L-homoserine lactone (OHHL); (E)
N-octanoyl-L-homoserine lactone (OHL); (F) N-(3-oxooctanoyl)-L-homoserine lactone (OOHL); (G)
N-(3-hydroxy-7-cis-tetradecenoyl)-L-homoserine lactone (HtdeDHL); (H)
N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL). I,J: Two microbial diketopiperazines: (I) cyclo( -Pro-L-Tyr); (J)
cyclo(ΔAla-L-Val). K: 2-Heptyl-3-hydroxy-quinolone (PQS). L: A furanone of Delisea pulchra,
4-bromo-5-(bromomethylene)-3-(1′-hydroxybutyl)-2(5H)-furanone. M: The butyrolactone putatively
produced by Xanthomonas campestris. N: 3-Hydroxypalmitic acid methyl ester (3OH PAME).
Structure and function of LuxI-type acyl-homoserine-lactone (acyl-HSL) synthases. Residues conserved in all LuxI-type proteins are labelled with an asterisk. Residues whose mutation in LuxI and RhlI results in significant loss of activity are shown in red; residues for which inactivating mutations have been isolated in LuxI only are
shown in blue; residues for which an inactivating mutation has been isolated in RhlI only are shown in green. The threonine residue that is conserved in LuxI homologues that synthesize 3-oxo-acyl-HSL derivatives is shown in grey. Numbering is relative the LuxI sequence. Blue and red bars define the areas that are proposed to be involved in catalysis and specificity, respectively. [Fuqua C. et al., 2002. Nature Rev./Molecular Cell Biol. 3:685-695]
N H2 CH
CH2
CO2H
CO2H
N H2 CH
CH2
CO2H
COPO3 O
N H2 CH
CH2
CO2H
CHO
N H2 CH
CH2
CO2H
CH2OH
N H2 CH
CH2
CO2H
CH2OPO3
N H2 CH
CH2
CO2H
CH3 O O N H2 N N N N NH2 O OH OH O N H2 O S C H3 Aspartate Aspartyl phosphate Aspartate semialdehyde Homoserine Homoserine phosphate Threonine Homoserine lactone Lysine Methionine Isoleucine S-adenosyl methionine + .. .. _
(?)
ATPPi + PPi
Model of acyl-homoserine-lactone (acyl-HSL) quorum sensing in a single generalized bacterial cell.
Tentative mechanisms for acyl-HSL synthesis and acyl-HSL interaction with LuxR-type proteins are shown. Double arrows with filled yellow circles at the cell envelope indicate the potential two-way diffusion of acyl-HSLs into and out of the cell. The proposed dimerization of LuxR (red) is based on genetic evidence and biochemical analysis of TraR; other LuxR-type proteins might form higher-order multimers. Binding of the acyl-HSL to LuxR and multimerization are represented as distinct events, although they might occur simultaneously. The LuxI label indicates LuxI-type proteins. 5'-MTA, 5'-methylthioadenosine; ACP, acyl carrier protein; SAM, S-adenosylmethionine. Modified with permission from Ref. 22 © (2001) Annual Reviews.
Stereo view of the structure of the TraR
–
OOHL
–
DNA complex. Domains in the two monomers
are shown in different colours (light/dark orange and light/dark green), whereas the DNA is
coloured blue and the OOHL is coloured red. Note that the two-fold dyad axis of the DNA and
DNA-binding domains lies in the plane of the page (horizontal red line), whereas that relating
to the pheromone-binding domains is swiveled by approximately 90° (short red line). Side
chains of residues in the upper monomer (light/dark green) that mediate interaction between
DNA-binding and pheromone-binding domains are shown in red and residues that affect
Modular structure of
Vibrio fischeri
LuxR protein
A
(2-20th a.a.)
region for the negative autoregulation of LuxR
B
(79-127th a.a.)
binding region for the acylated homoserine lactone
C
(116-161st a.a.)
multimerization site of 2 LuxR proteins
D
(193-197th a.a.)
putative transcriptional activation element
E
(200-220th a.a.)
helix-turn-helix DNA-binding motif
F
(240-250th a.a.)
region for LuxR-dependent transcription of
lux
operon
N-terminus C-terminus
..
C
N
A
R
C
S
T
T
G
G
V
T
A
A
G
X
G
G
A
A
T
T
C
N
G
X
T
T
A
R
C
C
A
A
G
S
G
R
T
T
V. fischeri
MJ1
lux
box
lux
box-like consensus sequence
The pheromone-binding site.
a
, Surface around the pheromone, which is coloured by the pK
(red for acidic and blue for basic residues) of the residues of the pheromone-binding cavity.
b
,
Four hydrogen bonds between the pheromone and TraR. The hydrogen bond between the
3-keto group and protein is water-mediated. The distance between interacting atoms is shown in
Vibrio fischeri lux
-gene organization and symbiotic bioluminescence
Examples of signaling molecules used for bacterial quorum sensing regulation. The figure shows the names and principal structures of quorum sensing molecules and lists their producers as well as their sensing mechanisms.
The three steps in quorum sensing regulation. (1) In the first step, the signaling molecules are produced either by employing the intracellular machinery and subsequent outward-bound transport or by secreting a protease and subsequent cleavage from bacterial or even adjacent host structures. The signaling molecules may stay bound to the bacterial surface or could be secreted to the environment. (2) In the second step, the signaling molecules accumulate outside the bacteria either due to the continuous production of a growing number of bacteria, a decrease of available space even without further production of signaling molecules, or due to the vicinity of an impermeable structure in combination with a low level production of the molecules. (3) In the third step, the
signaling molecules reach a threshold level, at which it is sensed at the bacterial surface or after passive or active passage through the cell membrane by intracellular receptors. As a consequence, specific regulators will be
activated and start their quorum sensing control of gene expression. [Podbielski A. et al., 2004. Int J Infect Dis. 8(2):81-95.]
Introduction
–
three steps in
Quorum-sensing
vs
. central metabolism
AI 2;
furanosyl borate diester
bioluminescence (
V. harveyi
)
ABC transporter (
S. typhimurium
)
type III secretion (EH
EC
)
virulence factor, VirB (
S. flexneri
)
protease (
S. pyogenes
)
in vivo
fitness (
N. meningitidis
)
Chen et al., 2002. Nature
415: 545 -
549
The autoinducer AI-2, synthesized by LuxS, is bound by the sensor protein LuxP. a, Biosynthesis of the AI-2 precursor 4,5-dihydroxy-2,3-pentanedione (DPD) from S-adenosylmethionine9–13. b, Induction of bioluminescence in the V.
harveyi bioassay13 was measured following the addition of the products of an in vitro reaction of S
-adenosylhomocysteine with Pfs and LuxS proteins13, reaction buffer, or AI-2 released from LuxP overproduced in
LuxS+ or LuxS- E. coli BL21. Concentrations of AI-2 in the Pfs/LuxS and LuxP (BL21) reactions were estimated to be
Structure of LuxP-AI-2 complex. a, Overview. b–d, Fo - Fc difference electron density (contoured at 4 ) calculated using phases derived from the model before AI-2 addition. The final refined model for AI-2 is shown superimposed on this density. Boron, oxygen, nitrogen and carbon are coloured yellow, red, blue and grey, respectively. In the
stereoviews shown in c–d, hydrogen bonds are shown as dashed red lines. Figure prepared using O26, Molscript28/
Bobscript29 and Raster 3D30.
Quorum-Sensing in (Eu)bacterial Systems
Bioluminescence:
Vibrio fischeri, V. harveyi
Symbioses:
V. fischeri
Biofilm architecture:
Pseudomonas aeruginosa
Virulence:
Erwinia stewartii, P. aeruginosa
Antibiotics/exoenzyme release:
Chromobacterium
violaceum,
Erwinia carotovora, Pseudomonas aurefaciens, Streptomyces
spp
.
Conjugation:
Agrobacterium tumefaciens
Cell division:
E. coli
(Social gliding) Motility:
Serratia liquifaciens
Stationary phase-related:
Rhizobium leguminosarum
Lag phase-related:
Nitrosomonas europea
Competence:
Streptomyces
spp
. Bacillus
spp
.
Antibiotic resistance
Antibiotic
Antibiotic
Antibiotic sensitive bacteria
Antibiotic resistant bacteria
Now a days most of bacteria are antibiotic resistant
Strategies for quorum sensing inhibition
3 strategies can be applied
Targeting AHL signal
dissemination
Targeting the signal
receptor
Targeting signal
generation
Signal precursor
Signal
Signal receptor
Signal precursor
Signal precursor
Signal
Signal
Signal receptor
Signal receptor
X
Targeting signal generation
Signal generation can be inhibited by using analogue of precursor of
signal molecule.
AHL signals are generated from precursors : acyl –ACP and SAM.
Analogues of acyl-ACP and SAM can be used to reduce synthesis of
quorum sensing signals.
Effect of substrate analogues on RhlI
activity in
P. aeruginosa
Inhibitors
Inhibition,%
In
P. aeruginosa
RhlI acts as autoinducer synthase
Targeting AHL signal dissemination
QS molecules can be degraded by:
Increasing pH (>7): as at higher pH AHL molecules undergo lactonolysis
in which its biological activity is lost.
At higher temperature AHL undergoes lactonolysis.
Some plants infected by pathogenic bacteria
E. carotovora
, increase the
pH at the site of infection, resulting in lactonolysis of AHL molecules.
Some bacteria produces lactonolysing enzymes, such as AiiA.
Eg:
Bacillus cereus, B. thuriengiensis
.
AiiA as antipathogenic agent
Potato Tobacco
Tobacco lines
expressing AiiA
Corresponding Wild-
type Tobacco sps.
Potato lines
expressing AiiA
Corresponding Wild-
type Tobacco sps.
Targeting the signal receptor
Targeting QS signal receptor by the QS antagonists is highly
investigated and promising strategy.
Several AHL analogues have been synthesized which binds with
receptor/DNA transactivator, LuxR, but this complex is not activated,
which can not activate virulence genes expression.
Some analogues have been synthesized by substitutions in HSL ring or
in acyl side chain and in some analogues HSL ring has been replaced by
alternative rings.
Rasmussen et al. (2005), screened several QSIs among natural and
synthetic compound libraries.
The two most active were garlic extract and 4-nitro-pyridine-
N
-oxide
(4-NPO).
Microarrays analysis revealed that garlic extract and 4-NPO reduced
QS-controlled virulence genes in
Pseudomonas aeruginosa
.
These two QSIs also significantly reduced
P. aeruginosa
biofilm
tolerance to tobramycin treatment as well as virulence in a
Caenorhabditis elegans
pathogenesis model.
Future perspectives
Q S inhibitors have provided evidence of alternative method for fighting
bacterial infections.
QS inhibitors can be isolated from the huge natural pool of chemicals.
Most compounds are unsuitable for human use.
We are lacking in selection of human compatible QS inhibitors.
