INFECTION AND IMMUNITY,
Copyright © 2000, American Society for Microbiology. All Rights Reserved.
Sept. 2000, p. 4839–4849Vol. 68, No. 9
Bacterial Quorum Sensing in Pathogenic Relationships
TERESA R. DE KIEVIT AND BARBARA H. IGLEWSKI*
University of Rochester School of Medicine and Dentistry, Rochester, New York 14642
Bacteria were for a long time believed to exist as individual
cells that sought primarily to find nutrients and multiply. 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 adopt
new modes of growth, such as sporulation or biofilm formation,
which may afford protection from deleterious environments.
The “language” used for this intercellular communication is
based on small, self-generated signal molecules called autoin-
ducers. Through the use of autoinducers, bacteria can regulate
their behavior according to population density. The phenom-
enon of quorum sensing, or cell-to-cell communication, relies
on the principle that when a single bacterium releases autoin-
ducers (AIs) into the environment, their concentration is too
low to be detected. However, when sufficient bacteria are
present, autoinducer concentrations reach a threshold level
that allows the bacteria to sense a critical cell mass and, in
response, to activate or repress target genes. Most of the bac-
teria thus far identified that utilize quorum-sensing systems are
associated in some way with plants or animals. The nature of
these relationships can be either amicable, as characterized by
symbiotic bacteria, or adversarial, as seen with pathogenic bac-
teria. There are numerous bacteria that have components of a
quorum-sensing system for which the phenotype regulated re-
mains an enigma. Similarly, there are bacteria known to reg-
ulate a specific phenotype via quorum sensing for which one or
more of the regulatory components have thus far eluded iden-
tification. In this review we give examples of pathogenic rela-
tionships, focusing on organisms for which many of the facets
of their quorum-sensing systems have been elucidated.
QUORUM SENSING IN GRAM-NEGATIVE BACTERIA
The vast majority of gram-negative quorum-sensing systems
that have been studied thus far utilize N-acyl homoserine lac-
tones (AHL) as signaling molecules. When in high enough
concentration, these molecules can bind to and activate a tran-
scriptional activator, or R protein, which in turn induces ex-
pression of target genes (Fig. 1). The use of biosensors to
screen spent culture supernatants has led to the discovery that
AHLs are produced by a plethora of unrelated bacteria (Table
1). Biosensors typically consist of a quorum-sensing-controlled
promoter fused to a reporter such as lacZ or the lux operon.
These biosensor strains contain a functional R protein but lack
the AHL synthase enzyme; therefore, promoter activity de-
pends on the presence of exogenous AHL. Despite the fact
that R proteins 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 noncognate AHL are usually required for
activation. To date, AHL molecules have been identified con-
taining 4- to 14-carbon acyl side chains and either an oxo, a
hydroxy, or no substitution at the third carbon. Only two AHLs
bearing double bonds have been identified: 7,8-cis-N-(3-hy-
droxytetradecenoyl)homoserine lactone from Rhizobium legu-
minosarum (47, 105) and 7,8-cis-N-(tetradecenoyl)homoserine
lactone from Rhodobacter sphaerhoides (92).
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 (34). Xan-
thomonas campestris pv. campestris, a cabbage pathogen, pro-
duces a diffusible extracellular factor (DSF) which has yet to be
chemically characterized but is not an AHL (5). In Pseudomo-
nas aeruginosa, a third autoinducer, designated PQS (Pseudo-
monas quinolone signal), was identified that is distinct from the
other two AHL autoinducers produced by this organism in that
it is a 2-heptyl-3-hydroxy-4-quinolone (82). Butyrolactones
have been isolated from Pseudomonas aureofaciens culture su-
pernatants (41), and recently, a novel family of signaling com-
pounds, identified as diketopiperazines (DKPs), were discov-
ered in cell-free supernatants of P. aeruginosa, Pseudomonas
fluorescens, Pseudomonas alcaligenes, Enterobacter agglomer-
ans, and Citrobacter freundii (49). Although these molecules
were capable of only weakly activating a number of LuxR-
based biosensors, some of the DKPs were able to act antago-
nistically to reduce N-3-(oxohexanoyl)homoserine lactone (3-
oxo-C6-HSL)-mediated bioluminescence, suggesting that they
may be able to compete for LuxR binding. In nature, DKPs
have been isolated from a wide range of sources and have been
shown to have pharmacological effects in various mammals,
including humans (91); however, the precise role played by
DKPs in bacterial cell-to-cell signaling has yet to be estab-
With regard to bacteria that utilize quorum sensing as part
of their pathogenic lifestyle, P. aeruginosa is perhaps the best
understood in terms of the virulence factors regulated and the
role quorum sensing plays in pathogenicity. Classified as an
opportunistic pathogen, P. aeruginosa primarily infects individ-
uals who are immunocompromised, such as patients with can-
cer or AIDS (33, 68) or those having breaches in normal
barriers caused by burns, indwelling medical devices, or pro-
longed use of broad-spectrum antibiotics (11, 23). P. aerugi-
nosa has an impressive armament of both cell-associated and
* Corresponding author. Mailing address: Department of Microbi-
ology and Immunology, Box 672, Strong Memorial Hospital, Univer-
sity of Rochester, Rochester, NY 14642. Phone: (716) 275-3402. Fax:
(716) 473-9573. E-mail: email@example.com.
extracellular virulence factors. Expression of many of the ex-
tracellular factors is not constitutive but rather cell-density
dependent with maximum protease production occurring dur-
ing the late logarithmic and early stationary phases of growth
(123, 124). The genetic basis for this growth-phase regulation
was uncovered with the discovery that P. aeruginosa contains
genes, called lasR and lasI, with significant homology to the
luxR and luxI genes of Vibrio fischeri (42, 76). In V. fischeri, luxR
and luxI are involved in the cell-density-dependent regulation
of light production (30, 109). The luxR gene encodes a tran-
scriptional activator of the bioluminescence operon, and luxI
codes for an autoinducer synthase that directs the synthesis of
the autoinducer 3-oxo-C6-HSL (26). Upon binding 3-oxo-C6-
HSL, the LuxR protein becomes activated, enabling it to in-
duce transcription of the lux operon. Since the discovery of the
lux quorum-sensing system, a number of gram-negative bacte-
ria, including P. aeruginosa, have been found to produce LuxR-
and LuxI-type proteins (for reviews, see references 39 and 40).
In P. aeruginosa, the transcriptional activator LasR functions
in conjunction with its cognate AHL, N-(3-oxododecanoyl)-L-
homoserine lactone (3-oxo-C12-HSL), synthesized by the LasI
autoinducer synthase (76, 78). LasR–3-oxo-C12-HSL regulates
expression of a number of P. aeruginosa virulence genes in-
cluding lasB, lasA, aprA, and toxA (42, 43, 78, 121) as well as
lasI itself, creating an autoinduction feedback loop (106) (Fig.
2). An additional gene, rsaL, is under the regulatory control of
LasR–3-oxo-C12-HSL, the product of which negatively regu-
lates P. aeruginosa quorum sensing by inhibiting lasI expression
The discovery of a second signaling system revealed that
quorum sensing in P. aeruginosa is more complex than origi-
nally believed (12, 73, 74, 126). The rhl quorum-sensing system
consists of the transcriptional activator RhlR and the autoin-
ducer synthase RhlI which directs the synthesis of N-butyryl-
L-homoserine lactone (C4-HSL) (79). The RhlR–C4-HSL com-
plex regulates expression of rhlAB, required for rhamnolipid
production, lasB, aprA, the stationary-phase sigma factor
RpoS, and production of the secondary metabolites pyocyanin
and cyanide (12, 60, 61, 73, 79, 126).
With the finding that P. aeruginosa has two separate quo-
rum-sensing circuits came the question of whether the two
were capable of interaction. In spite of the predicted structural
similarities between LasR and RhlR and the similarities be-
tween the two AHLs, there is little interchangeability between
the two systems. The R-proteins are not significantly activated
by their noncognate AHLs; LasR is not activated by C4-HSL
and 3-oxo-C12-HSL is capable of only low-level RhlR activa-
tion (80). Thus it appears that the R proteins show high spec-
ificity with regard to the AHL required for their activation.
Similarly, genes that are primarily activated by one system are
only minimally activated by the other (80), indicating that
specific recognition sequences must be present in the operator
regions of these target genes that dictate which quorum-sens-
ing system is required for induction. Despite the high fidelity of
these systems for their regulatory components and gene tar-
gets, a link between the two systems does exist. The las system
positively regulates expression of both rhlR and rhlI (60, 83)
(Fig. 2). Furthermore, 3-oxo-C12-HSL is able to compete with
C4-HSL for RhlR binding, indicating that 3-oxo-C12-HSL is
able to act as an antagonist of the rhl system (83). Thus, it
appears that in P. aeruginosa, quorum sensing is arranged in a
hierarchical fashion with the las system being the dominant
In addition to 3-oxo-C12-HSL and C4-HSL, which are the
major AHLs produced by P. aeruginosa grown in the labora-
tory, minor AHL products can also be detected (78). A com-
plete description of the AHL biosynthetic pathways is beyond
the scope of this review (for a review, see reference 37); how-
ever, the autoinducer synthase molecules examined to date
have been found to use S-adenosylmethionine and the appro-
priate fatty acid conjugated to acyl carrier protein (ACL) as
substrates. In P. aeruginosa, in vitro studies of AHL synthesis
have revealed that the majority, if not all, of the 3-oxo-HSLs
found in culture supernatants are synthesized by LasI (H.
Schweizer, personal communication). Furthermore, when one
of the enzymatic steps of the fatty acid biosynthetic pathway
becomes rate limiting, 3-oxo-C12-HSL is no longer produced at
detectable levels; instead, the shorter-chain-length HSLs
3-oxo-C10-HSL, 3-oxo-C8-HSL and 3-oxo-C6-HSL are prefer-
entially generated (H. Schweizer, personal communication).
These findings indicate that the acyl chain lengths of the HSL
products are at least in part regulated by the availability of the
3-oxo-acyl-ACP substrate precursors.
To date, the biological function of these noncognate AHLs
remains an enigma. One possible role for these minor AHL
molecules is to activate additional LuxR-type proteins. In P.
aeruginosa, two genes encoding proteins with significant ho-
mology to LasR and RhlR have been identified; however, at
this time it is unclear whether the minor signal molecules
present in P. aeruginosa culture supernatants can activate ei-
ther of these R proteins. A second possible role for noncognate
AHLs arises from the fact that these molecules can frequently
activate a given R protein, albeit at lower induction levels than
for the cognate AHL. In this manner, minor AHLs may func-
tion as competitive inhibitors of autoinduction. An example of
this is seen in P. aeruginosa where the las signal molecule
3-oxo-C12-HSL can efficiently compete with C4-HSL for RhlR
binding (83). Similarly in V. fischeri, a second AHL synthase,
AinS, directs the synthesis of N-octanoyl-L-HSL (C8-HSL)
(59). Despite the fact that C8-HSL can activate LuxR to some
degree, it appears that this molecule functions as a competitive
inhibitor of V. fischeri bioluminescence. In ainS mutants, in-
duction of bioluminescence occurs at a lower cell density than
in the parental strain (59). Furthermore, addition of C8-HSL to
cultures of either the wild-type strain or ainS mutants results in
delayed onset of bioluminescence (59). Thus, in both P. aerugi-
FIG. 1. Quorum sensing in gram-negative organisms involves two regulatory
components: the transcriptional activator protein (R protein) and the AI mole-
cule produced by the autoinducer synthase. Accumulation of AI occurs in a
cell-density-dependent manner until a threshold level is reached. At this time the
AI binds to and activates the R protein, which in turn induces gene expression.
The R protein consists of two domains: the N terminus of the protein that
interacts with AI and the C terminus that is involved in DNA binding. Typically,
gram-negative AI molecules are N-acyl-HSLs; however, other types of signal
molecules do exist.
nosa and V. fischeri, the inhibitory effect of noncognate AHLs
may represent a means of “fine tuning” these quorum-sensing
systems to precisely control expression of target genes.
Recently, a third autoinducer molecule was identified in P.
aeruginosa (82). This molecule is structurally very different
from the other two P. aeruginosa autoinducers in that it is a
2-heptyl-3-hydroxy-4-quinolone, designated PQS. Preliminary
studies have revealed that PQS is involved in lasB expression
and that although expression of PQS is under control of the las
system, RhlR is required for PQS activity. At present, many
aspects of PQS have yet to be uncovered, including the role it
plays in P. aeruginosa quorum sensing and virulence and the R
protein with which it reacts. The structural similarity between
PQS and antimicrobial quinolones is quite intriguing, although
preliminary studies have not shown any antimicrobial activity
associated with PQS (82). The discovery of PQS reveals yet
TABLE 1. Summary of quorum sensing in gram-negative bacteria
OrganismMajor signal molecule
Vibrio fischeri 3-Oxo-C6-HSLLuxI/LuxR Bioluminescence 26, 31
Bioluminescence 7, 8, 13, 108
Vibrio anguillarum? VanI/VanR 3-Oxo-C10-HSL69
Pseudomonas aeruginosa3-Oxo-C12-HSLLasI/LasRMultiple extracellular enzymes,
RhlR, Xcp, biofilm formation
Multiple extracellular enzymes,
rhamnolipid, RpoS, secondary
14, 19, 42, 43, 76, 78,
12, 61, 73, 74, 79, 126C4-HSL RhlI/RhlR
Pseudomonas aureofaciensC6-HSLPhzI/PhzR Phenazine antibiotics84, 85
Agrobacterium tumefaciens 3-Oxo-C8-HSL TraI/TraR Ti plasmid conjugation51, 87, 130
Erwinia carotovora subsp.
3-Oxo-C6-HSLExpI/ExpR Exoenzymes 4, 16, 55, 65, 88
CarI/CarR Carbapenem antibiotics
Erwinia chrysanthemi 3-Oxo-C6-HSL
ExpI/ExpR Pectate lyases72, 98
Erwinia stewartii 3-Oxo-C6-HSLEsaI/EsaR Exopolysaccharide, virulence factors9
Rhizobium leguminosarumC6-HSLRhiI/RhiR RhiABC rhizosphere-expressed
18, 47, 99
Rhizobium etli? RaiI/RaiRRestriction of number of nitrogen-
Chromobacterium violaceumC6-HSL CviI/CviRExoenzymes, antibiotics, cyanide,
Burkholderia cepaciaC8-HSL CepI/RProtease, siderophores62
Aeromonas hydrophilaC4-HSL AhyI/AhyRExoprotease production 114
Aeromonas salmonicidaC4-HSL AsaI/AsaR Extracellular protease114
Ralstonia solanacearumC8-HSLSolI/SolR? 35
Serratia liquifaciensC4-HSL SwrI/SwrR Extracellular protease, swarming27, 44
Rhodobacter sphaeroides 7-cis-C14-HSLCerI/CerR Dispersal from bacterial aggregates 92
Enterobacter agglomerans3-Oxo-C6-HSLEagI/EagR? 115
Escherichia coli? ?/SdiACell division, attachment and
effacing lesion formation
107, 110, 127
Yersinia enterocholiticaC6-HSL YenI/YenR? 120
Yersinia pseudotuberculosisC8-HSL YesI/YesR?3
VOL. 68, 2000 MINIREVIEW 4841
another layer in the increasingly complex system used by this
organism to maintain tight control of its virulence factors. This
tight regulation is a common theme in P. aeruginosa quorum
sensing, evidenced by the fact that the xcp genes involved in
type II secretion are under control of both the las and rhl
quorum-sensing systems (14). This pathway is utilized in secre-
tion of quorum-sensing controlled enzymes, such as elastase
and proteases, indicating that P. aeruginosa is extremely vigi-
lant about regulating these factors at both the levels of pro-
duction and export.
P. aeruginosa is intrinsically resistant to numerous antimi-
crobial agents, including antibiotics, organic solvents, and de-
tergents. Low outer membrane permeability together with the
presence of multidrug efflux pumps that export a wide range of
antimicrobial agents is thought to contribute to this intrinsic
resistance. Three well-studied P. aeruginosa pumps have been
described: MexAB-OprM, MexCD-OprJ, and MexEF-OprN
encoded by the mexAB-oprM, mexCD-oprJ, and mexEF-oprN
operons, respectively (58, 89, 90). During a study to investigate
whether AIs freely diffuse in and out of P. aeruginosa cells, it
was discovered that in addition to its slow diffusion, 3-oxo-C12-
HSL is actively pumped from cells by the MexAB-OprM pump
(81). In contrast, C4-HSL diffuses rapidly across the cell mem-
branes and is not actively transported (81). Presumably, the
difference in the length of the acyl chains accounts for the
differences in cellular accumulation of the two AIs, with the
more hydrophobic 3-oxo-C12-HSL partitioning into the cyto-
plasmic membrane, thereby facilitating its export by the
MexAB-OprM pump. These findings are intriguing because
they suggest that antimicrobial therapy designed to interfere
with MexAB-OprM drug efflux will also affect las-controlled
gene expression. In cells lacking a functional MexAB-OprM
pump, a higher accumulation of 3-oxo-C12-HSL would be ex-
pected to occur sooner, which should result in earlier expres-
sion of target genes. It has been theorized that bacteria employ
quorum sensing for regulation of virulence to ensure that toxic
immune response-activating factors are elicited only after a
sufficient number of bacteria have been amassed to overwhelm
host defenses. If the bacteria are forced to prematurely pro-
duce virulence factors, the host may recognize the invading
bacteria sooner and eradicate the infection. Thus, antimicro-
bial strategies designed to disarm efflux pumps and increase
the antibiotic susceptibility of P. aeruginosa may prove even
more effective if they cause premature expression of virulence
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 patho-
genicity 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. aerugi-
nosa was found to have significantly decreased virulence com-
pared to that in the parent (117). Analysis of a 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 the double I mutant (77). 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
(101, 102). 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
parent strain (102). These findings indicate that quorum sens-
ing plays an important role in the dissemination of P. aerugi-
nosa throughout the body of burned mice. In the double I
mutant, which was the least virulent strain, complementation
with lasI, rhlI, or both lasI and rhlI on multicopy plasmid
significantly increased both in vivo virulence and the ability to
spread within the burned skin of the infected animals (102).
In a study employing three different models of infection,
namely Caenorhabditis elegans (nematode), Arabidopsis thali-
ana (plant), and a burned mouse model, a lasR-deficient mu-
tant generated through random mutagenesis exhibited greatly
reduced virulence in all three models (116). Intriguingly, a
gacA mutant and a toxA mutant also exhibited decreased vir-
ulence in the three models (93, 94, 116). GacA is a global
activator in P. aeruginosa that has previously been shown to
regulate expression of lasR and rhlR and production of the rhl
AHL, C4-HSL (97); toxA encodes exotoxin A, which is regu-
lated by the las quorum-sensing system (43). These studies are
extremely exciting because they suggest that the three afore-
mentioned genes, which are all linked to quorum sensing,
contribute to the trans-kindom 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. In the future,
it will be intriguing to see if other bacteria that infect multiple
FIG. 2. The quorum-sensing circuitry of P. aeruginosa is illustrated. Expres-
sion of the lasR gene is subject to at least two levels of control: the global
regulators Vfr and GacA (1, 97) and the las quorum-sensing system, which
regulates expression of both lasR and lasI. The latter creates an autoinduction
feedback loop. Regulation of the rhl system is similar to las in that GacA affects
expression of rhlR (97), and the rhlR and rhlI genes are controlled to some degree
by the las system. Interestingly, the las quorum-sensing system was shown to elicit
an additional level of control over the rhl system; the las signal molecule, 3-oxo-
C12-HSL, can act posttranslationally to block RhlR activation by C4-HSL. The
las and rhl quorum-sensing systems regulate expression of numerous genes that
contribute to the virulence of P. aeruginosa. In addition, the las signal molecule,
3-oxo-C12-HSL, is required for biofilm differentiation and exhibits immuno-
species and employ quorum sensing as part of their pathogenic
lifestyles have genes that contribute to virulence in such di-
In a study designed to assess the role of P. aeruginosa quo-
rum sensing in human infections, sputum samples from the
lungs of cystic fibrosis (CF) patients infected with P. aeruginosa
were assayed for lasR, lasA, lasB, and toxA expression (111). A
correlation was observed between lasA, lasB, and toxA tran-
script accumulation, suggesting coordinated regulation of
these genes. Moreover, accumulation of the lasR transcript
correlated with that of the other genes; thus, it appears that
LasR–3-oxo-C12-HSL actively regulates gene expression dur-
ing chronic lung infection.
BURKHOLDERIA CEPACIA: EVIDENCE OF A ROLE FOR
INTERSPECIES COMMUNICATION IN
B. cepacia (formerly Pseudomonas cepacia) has emerged as a
formidable pathogen in individuals with CF (46). In most in-
stances, patients colonized with B. cepacia are coinfected with
P. aeruginosa (118), and this has led to speculation whether
interspecies communication using P. aeruginosa AHLs can en-
hance the pathogenicity of B. cepacia. Addition of P. aerugi-
nosa-spent media to cultures of B. cepacia resulted in a sub-
stantial increase in both protease synthesis (twofold) and
siderophore production (sevenfold), suggesting the presence
of a quorum-sensing system (66). Subsequently, luxRI ho-
mologs have been identified in B. cepacia, called cepR and cepI
(62). The CepRI quorum-sensing system was found to have
both a positive and negative regulatory role in B. cepacia,
increasing protease production while simultaneously decreas-
ing siderophore synthesis (62). In culture supernatants, the
concentration of B. cepacia AHL, identified as C8-HSL, was
found to be 1,000-fold less than the concentration of 3-oxo-
C12-HSL and C4-HSL in P. aeruginosa culture supernatants
(62). Whether B. cepacia actually produces C8-HSL in minute
amounts or the conditions that were used for AHL production
were not optimal has yet to be determined. However, it is
possible that B. cepacia colonization of the CF lung succeeds
infection with other microorganisms, like P. aeruginosa, be-
cause B. cepacia can utilize the exogenous AHLs produced by
other bacteria to initiate infection. As such, B. cepacia repre-
sents an example of an organism that profits from the energy
investment made by others to regulate its own pathogenicity
and may provide evidence for communication between differ-
ent bacterial species.
E. carotovora is a phytopathogen that causes soft rot in a
variety of plants (6). The pathogenicity of E. carotovora de-
pends on the production of various plant tissue-degrading en-
zymes, including pectate lyases, polygalacturonase, cellulase,
and proteases. These enzymes are involved in maceration of
plant tissue necessary for bacterial colonization of the host.
Production of enzymes by only a few cells of E. carotovora
would not have an effect on the plant tissue, and more likely,
it would activate the plant phytodefense mechanisms. There-
fore, E. carotovora uses quorum sensing, which ensures that
exoenzyme production does not occur until sufficient bacterial
numbers have been achieved for successful tissue destruction
and evasion of plant defenses (55, 88). This regulation relies on
the LuxRI homologs ExpR and ExpI (55, 88) that control
expression of the tissue-macerating enzymes in a cell-density-
dependent manner. The exact roles of ExpR and its cognate
AHL, 3-oxo-C6-HSL, in exoenzyme regulation are not yet
clearly defined. Studies have shown that an expI mutant is
deficient in exoenzyme production and unable to macerate
plant tissues. In contrast, a mutation in expR does not affect
enzyme production, and surprisingly, overexpression of expR
results in decreased enzyme production (65). These findings
have led to the proposal that ExpR may act as a repressor of
exoenzyme synthesis by sequestering the levels of 3-oxo-C6-
HSL. E. carotovora quorum sensing is made even more com-
plex by the finding that synthesis of the broad-spectrum anti-
biotic carbapenem is regulated using a second quorum-sensing
system. Carbapenem production is regulated by CarR and
CarI; the latter catalyzes the synthesis of 3-oxo-C6-HSL (4, 16,
65). When sufficient 3-oxo-C6-HSL is present, it binds to and
activates CarR, enabling it to induce expression of the carbap-
enem biosynthetic genes. Since the release of nutrient-rich
constituents from the plant likely promotes the growth of com-
peting microflora, it appears that E. carotovora has developed
a sophisticated strategy to counteract this competition by co-
ordinating production of carbapenem with the tissue-macerat-
ing enzymes. Two additional regulatory systems, known as
RsmA and Aep, have recently been linked to the ExpR/I and
CarR/I quorum-sensing circuits. For more details on RsmA
and Aep, see reference 86.
A. tumefaciens is a pathogen that is capable of causing crown
gall tumors in plants through the transfer of oncogenic DNA
from its tumor-inducing Ti plasmid to the nuclei of the plant.
In addition to the vir genes required for plant transformation,
the Ti plasmids also contain a complete set of tra genes that
facilitate interbacterial transfer of the Ti plasmid (2, 32). Con-
jugation in A. tumefaciens is actually regulated by two different
signaling mechanisms; one is plant based and the other is
bacterium associated. The plant-produced signal regulating ex-
pression of the tra genes is a conjugal opine that is produced by
crown gall tumors. Opines act as a nutrient source for the
infecting bacteria, and production of these compounds is under
direction of the Ti-plasmid, as are the enzymes necessary for
the import and catabolism of these compounds by the bacteria.
The two types of Ti plasmids present in A. tumefaciens differ
with respect to the opine that acts as the conjugal signal.
Nopaline-type Ti plasmids are induced by agrocinopines A and
B (29), whereas conjugation of octopine-type Ti plasmids is
induced by octopine (56). The discovery that A. tumefaciens
produces a diffusible compound that dramatically stimulates
plasmid conjugation (129) together with the identification of a
regulator, called TraR, capable of activating expression of the
tra genes (87) suggested that conjugal transfer in A. tumefa-
ciens is regulated by a quorum-sensing system. The bacterial
compound that stimulated conjugation was identified to be
3-oxo-C8-HSL (130) which is synthesized by the autoinducer
synthase TraI (51). TraR–3-oxo-C8-HSL regulates expression
of the tra regulon as well as the traI gene itself, thereby creating
a positive feedback loop (2, 32, 51, 87). An additional gene,
traM, positively regulated by TraR–3-oxo-HSL was found to
play a role in A. tumefaciens quorum sensing (50). Overexpres-
sion of traM on a multicopy plasmid in the presence of wild-
type levels of TraR abolished tra gene expression. However,
upon overexpression of TraR, tra gene expression was re-
stored, suggesting that TraM may interact stoichiometrically
with TraR to act as an antagonist of the tra regulon.
The A. tumefaciens opine and quorum-sensing signal path-
ways are linked to one another in a hierarchical fashion, with
opines being the dominant regulator. For TraR–3-oxo-C8-HSL
VOL. 68, 2000MINIREVIEW4843
signaling to occur, the appropriate opine must be present. In
the octopine-type Ti plasmids, this control is mediated by plac-
ing the traR gene under regulatory control of an octopine-
responsive activator, called OccR (38). It is only when suffi-
cient octopine is present that OccR induces transcription of
traR. After the cell density has increased to the point where
sufficient 3-oxo-C8-HSL has accumulated to activate TraR, the
tra operon is expressed. In the case of the nopaline-type Ti
plasmids, the traR gene is also regulated by opines but through
a different mechanism. Agrocinopines A and B induce expres-
sion of the traR gene; while a mutation in accR, which is
believed to encode a repressor, causes constitutive tra gene
expression (10). These findings have led to the proposal that
AccR directly represses traR expression and that the agroci-
nopines can act as antagonists of this repression (125).
QUORUM SENSING IN GRAM-POSITIVE ORGANISMS
A number of gram-positive bacteria are known to employ
quorum-sensing systems. The nature of the signal molecules
used in these systems differs from those of gram-negative or-
ganisms, and thus far, no gram-positive bacteria have been
shown to produce AHLs. Gram-positive quorum-sensing sys-
tems typically make use of small posttranslationally 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 faeca-
lis, and virulence in Staphylococcus aureus (24, 57). S. aureus
causes a wide range of disease states that range from mild to
life-threatening. The virulence of this organism is dependent
on the 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-1, be-
ta-hemolysin, and enterotoxin (25, and references therein).
During the early stages of S. aureus infection, surface proteins
involved in attachment (collagen- and fibronectin-binding pro-
tein) and defense (protein A) predominate. However, once a
high cell density is achieved at the infection site, expression of
S. aureus surface proteins is decreased and secreted proteins
are preferentially expressed. The genetic basis for this tempo-
ral gene expression depends on two pleiotropic regulatory loci
called agr (accessory gene regulator) (71, 96) and sar (staphy-
lococcal accessory gene regulator) (15).
The agr locus consists of two divergently transcribed oper-
ons, RNAII and RNAIII (52, 53) (Fig. 3). 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 RNAIII operon encodes a ?-hemolysin and is
itself a regulatory RNA that plays a key role in the agr re-
sponse. During S. aureus quorum sensing, the AgrC signal
transducer is autophosphorylated in response to the octopep-
tide signal molecule, which in turn leads to the phosphoryla-
tion of the AgrA response regulator (63). Phosphorylated
AgrA stimulates transcription of RNAIII and RNAIII, in turn,
upregulates expression of numerous S. aureus exoproteins as
well as the agrBDCA locus (52, 53). The latter leads to a rapid
increase in the synthesis and export of the octopeptide signal
molecule. At the second regulatory locus, the sar gene product
(SarA) functions as a regulatory DNA-binding protein to in-
duce expression of both the RNAII and RNAIII operons of
the agr locus (95).
EXPLOITING BACTERIAL QUORUM SENSING
Quorum sensing, 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 pro-
duction makes it an attractive target for antimicrobial therapy.
Through blocking this cell-to-cell signaling mechanism, patho-
genic organisms that use quorum sensing to control virulence
could potentially be rendered avirulent. Several possible ways
of interrupting the quorum-sensing circuitry exist; for example,
as described earlier, autoinducers and R proteins have a
unique specificity for one another. Noncognate autoinducers
typically only weakly activate or may inhibit R protein activa-
tion all together. Therefore, analogs that bind to but do not
activate R proteins could act as antagonists to prevent autoin-
ducer binding, which in turn would shut down the quorum-
sensing cascade. The ability of autoinducer analogs to inhibit
activation of R proteins has already been demonstrated in a
number of bacteria, including V. fischeri, A. tumefaciens, Chro-
mobacterium violaceum, and Aeromonas salmonicida (69, 103,
114, 131). Examples of this inhibition have been found to exist
in nature. In P. aeruginosa, 3-oxo-C12-HSL is able to antago-
nize RhlR activation by C4-HSL, and production of C8-HSL by
V. fischeri delays the onset of bioluminescence, presumably by
competing with 3-oxo-C6-HSL for LuxR binding. Moreover
the seaweed Delisea pulchra produces furanone compounds,
structurally similar to AHLs, that are capable of interfering
with the quorum-sensing systems of Serratia liquefaciens, V.
fischeri, and Vibrio harveyi (45).
In an exciting recent report, an enzyme from an isolate of
FIG. 3. Quorum sensing in S. aureus is depicted. The agr locus consists of two
divergent transcriptional units. One operon (agrBDCA) encodes the proteins
responsible for generating and sensing the peptide signal molecule (AgrD), and
the other encodes ?-hemolysin and RNAIII. The signal molecule is an octapep-
tide cleaved from the middle of the agrD gene product and is exported from the
cell via the membrane-associated AgrB protein. Once the extracellular concen-
tration of AgrD reaches a threshold level, it stimulates autophosphorylation of
the transmembrane AgrC protein, which in turn phosphorylates the response
regulator (AgrA). In its phosphorylated state, AgrA activates expression of
RNAIII. The rise in the level of regulatory RNAIII leads to increased secretion
of numerous factors, reduced expression of specific surface proteins, and induced
expression of the agrBDCA operon. SarA is a DNA-binding protein, encoded by
the sar locus, that upregulates expression of both agr operons.
4844 MINIREVIEWINFECT. IMMUN.
Bacillus that is capable of degrading AHLs was discovered
(22). This enzyme is encoded by the aiiA gene (autoinducer
inactivation) and contains two domains that are homologous to
the active sites of the following metalloenzymes: glyoxalase II,
metallo?-lactamase, and arylsulfatase (22). Expression of aiiA
in E. carotovora decreased generation of pectolytic enzymes
and significantly reduced AI production. Even more notewor-
thy was the finding that expression of the AiiA enzyme in E.
carotovora attenuated soft rot disease on all of the plants tested
(22). In the future it may be possible to confer resistance to
soft-rot and other diseases brought on by bacteria that regulate
virulence via autoinduction by providing plants with the aiiA
As a third means of interfering with quorum sensing, the
biosynthetic pathways of some AHL molecules have been elu-
cidated (48, 54, 70, 104). 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.
In organisms that employ more than one quorum-sensing
system for virulence regulation, it may be necessary to disarm
all of the systems present to attenuate virulence. This was
found to be the case with P. aeruginosa. In this organism, the
las quorum-sensing system controls expression of the rhl sys-
tem, suggesting that shutting down the las circuit should be
sufficient to abolish quorum-sensing regulated virulence factor
production. However, after growth under high stress condi-
tions, spontaneous mutants of a lasR-deficient strain capable of
elastase and rhamnolipid production were isolated (122).
Analysis of one of these mutants, PR1-E4, revealed increased
rhlI expression relative to the parent and likely accounts for the
increased production of rhamnolipid and elastase (122). Con-
versely, when both the las and rhl systems were nonfunctional,
mutants with restored production of virulence factors could
not be recovered. These findings suggest that for P. aeruginosa,
therapeutic strategies will have to target both the las and the
rhl quorum-sensing systems to be most effective.
Recently, quorum sensing was found to regulate expression
of the type III secretion systems of both enterohemorrhagic
Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC)
(110). Detection of AI molecules produced by E. coli was first
reported because of the ability of these signals to activate one
of the two V. harveyi quorum-sensing systems, called the auto-
inducer 2 (AI-2) system (112). Subsequently, synthesis of AI-2
was shown to be dependent on the luxS gene (113) and homo-
logues of luxS have been identified in a number of gram-
negative and gram-positive bacteria (113). Outside of V. har-
veyi and now EHEC and EPEC, little is known about the
functions that are controlled by this class of signaling mole-
cules. Both EHEC and EPEC interact with intestinal epithelia
to cause attaching and effacing lesions. These lesions result
from gene products encoded by a pathogenicity island called
the locus of enterocyte effacement (LEE) (28, 64), which en-
codes a type III secretion system and other products involved
in lesion formation. Using lacZ fusions, it was discovered that
the majority of the LEE-encoded genes were quorum-sensing
regulated (110). These findings suggest that strategies designed
to interfere with quorum sensing may be useful for treating and
preventing the devastating effects of EPEC and EHEC infec-
tions. Furthermore, many gram-negative bacteria employ both
quorum-sensing and type III secretion systems, and one might
speculate that these two systems are intimately associated,
both with each other and with the regulation of virulence in
many pathogenic bacteria.
Quorum sensing and biofilm formation. In nature, bacteria
are frequently found encased in a polysaccharide matrix at-
tached 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. P.
aeruginosa is an example of an organism frequently found
growing in biofilms. Microscopic analysis of P. aeruginosa bio-
film communities reveals that they are not just sugar-encased
masses of cells. Rather distinct mushroom and stalk-like struc-
tures that contain intervening water channels to allow nutrients
to flow in and waste products to flow out are present. Because
they pose problems of both medical and industrial importance,
the ability of bacteria, such as P. aeruginosa, to form biofilms is
of profound interest. In the clinical setting, biofilms formed on
medical devices and in bacterial infections can wreak havoc,
largely because bacteria growing as a biofilm are refractile to
host defenses including phagocytes, antibodies, and comple-
ment (17). Moreover, these organisms are highly resistant to
antibiotics, making eradication by using conventional chemo-
therapy virtually ineffectual. These findings underscore the
need to find novel ways of preventing biofilm formation and
eradicating those already established. Recently, a link between
biofilm formation and quorum sensing was discovered in P.
aeruginosa. Analysis of biofilms formed by a P. aeruginosa mu-
tant 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 (19). 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 bio-
film 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 if other bacteria use quorum sensing during
biofilm formation; however these findings suggest that, at least
in the case of P. aeruginosa, strategies designed to block quo-
rum sensing may be an effective means of preventing biofilm
Quorum sensing as a means of biological control in agri-
culture. Many plant-associated bacteria employ quorum sens-
ing for regulation of specific phenotypes as part of their patho-
genic or symbiotic lifestyles. As such, the ability to block or
promote these quorum-sensing systems may offer new strate-
gies for managing plant diseases and increasing crop produc-
tivity. In a recent study in which plants were genetically mod-
ified to produce AHLs, the feasibility of using plant-produced
AHLs to manipulate bacterium-plant associations was realized
(36). In these studies, plasmids containing the Yersinia entero-
colitica yenI gene were expressed in the chloroplasts of tobacco
plants. YenI directs the synthesis of C6-HSL and 3-oxo-C6-
HSL in a 1:1 ratio, and these compounds are the cognate
AHLs for the plant symbiont P. aureofaciens and the plant
pathogen E. carotovora, respectively. E. carotovora, as dis-
cussed earlier, is classed as a plant pathogen due to its quorum-
sensing-regulated production of plant-degrading enzymes. In
contrast, P. aureofaciens 30-84 is a symbiotic bacterium that
can protect wheat from take-all, a disease caused by the fungus
Gaeumannomyces graminis var. tritici (85). P. aureofaciens
30-84 produces three phenazine antibiotics that contribute to
this disease suppression, production of which is regulated by
the PhzR/I quorum-sensing system (84, 128).
Intriguingly, Fray and coworkers (36) discovered that AHLs
diffused from the chloroplastic organs of the tobacco plant and
from the roots as well. The plant-produced AHLs induced
bioluminescence in an E. coli strain containing an AHL-acti-
vated lux reporter. Furthermore, the AHLs restored the anti-
VOL. 68, 2000MINIREVIEW 4845
fungal activity of a “disarmed” P. aureofaciens 30-84 phzI strain
and enabled an avirulent E. carotovora carI mutant to infect
the transgenic plants (36). Thus, the plant-produced AHLs
appear to behave in a manner similar to that of their bacterial
The benefits of using plant-produced AHLs for modifying
the behavior of symbiotic bacteria are clear. For example,
these AHLs could be used to promote an antifungal environ-
ment by P. aureofaciens, or alternatively, they might enhance
the ability of nitrogen-fixing bacteria such as rhizobial species.
In the case of pathogenic E. carotovora, the ability to regulate
expression of plant-degrading enzymes in a cell-density-depen-
dent manner is believed to contribute to the virulence of this
organism. It is only after high cell densities have been achieved
that the bacteria are able to successfully compete with the
plant host defenses. If the production of plant-degrading en-
zymes were induced prematurely, when bacterial numbers
were low, then the plant might be able to mount an effective
defense. Indeed, resistance to E. carotovora infection has been
observed in plants treated with salicylic acid, which induces the
plant phytodefense system (75). Therefore, production of
AHLs in plants that are hosts for E. carotovora, such as pota-
toes and carrots, may afford protection from the consequences
of bacterial infection.
The ability to coordinate behavior in a cell-density-depen-
dent fashion has several obvious advantages. In the case of
pathogenic microorganisms, the regulation of virulence deter-
minants throughout the infection process is believed to play an
important role in pathogenicity. Evading host defenses is a
major goal of pathogens, and as such, quorum sensing is an
important asset because it enables bacteria to appropriately
time expression of immune response-activating products. Us-
ing quorum sensing, bacteria can amass a high cell density
before virulence determinants are expressed, and in so doing,
the bacteria are able to make a concerted attack and produce
ample virulence factors to overwhelm the host defenses.
In this minireview we have discussed the diverse role of
AHL signaling molecules in bacterial cell-to-cell communica-
tion, as well as their potential role in the interaction of bacteria
with eucaryotic hosts. To think that these AHL molecules,
which readily diffuse across cell membranes, have no direct
effect on the eucaryotic cells is somewhat naı ¨ve. Indeed evi-
dence exists to suggest that these AHL signal molecules inter-
act directly with eucaryotic cells to modulate host immune
responses. As an example, the P. aeruginosa AHL 3-oxo-C12-
HSL was shown to elicit interleukin-8 production in a respira-
tory epithelial cell line (21). Because interleukin-8 is a neutro-
phil chemoattractant, it seems improbable that this response
affords any benefit to P. aeruginosa. It is more likely the AHL
is having the unintentional effect of acting as a signal to warn
the host of the presence of this bacterium. In another study,
Telford and coworkers (119) discovered that 3-oxo-C12-HSL
suppressed release of interleukin-12 and tumor necrosis factor
alpha from lipopolysaccharide-stimulated macrophages. In this
instance, 3-oxo-C12-HSL may be behaving as a virulence factor
directly, by modulating the inflammatory responses of the host.
The ability of these signal molecules to act as virulence deter-
minants themselves suggests a possible role for AHLs pro-
duced by organisms for which a quorum-sensing-regulated
phenotype has not been ascribed, such as in Yersinia.
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 impor-
tant animal and plant pathogens use quorum sensing to regu-
late virulence, strategies designed to interfere with these sig-
naling 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. The discovery that P.
aeruginosa uses quorum sensing to regulate biofilm production
suggests that agents capable of blocking quorum sensing may
also be useful for preventing biofilm formation. The recent
production of AHLs in plants represents an exciting new ap-
proach to controlling crop diseases as well as to manipulating
plant-microbe interactions for improved crop production in
1. Albus, A. M., L. J. Runyen-Janecky, S. E. H. West, and B. H. Iglewski. 1997.
Vfr controls quorum sensing in Pseudomonas aeruginosa. J. Bacteriol. 179:
2. Alt-Mo ¨rbe, J., J. L. Stryker, C. Fuqua, S. K. Farrand, and S. C. Winans.
1996. The conjugal transfer system of A. tumefaciens octopine-type Ti-
plasmids is closely related to the transfer system of an IncP plasmid and
distantly related to Ti plasmid vir genes. J. Bacteriol. 178:4248–4257.
3. Atkinson, S., J. P. Throup, G. S. Stewart, and P. Williams. 1999. A hier-
archical quorum-sensing system in Yersinia pseudotuberculosis is involved in
the regulation of motility and clumping. Mol. Microbiol. 33:1267–1277.
4. Bainton, N. J., P. Stead, S. R. Chhabra, B. W. Bycroft, G. P. C. Salmond,
G. S. A. B. Steward, and P. Williams. 1992. N-(3-Oxohexanoyl)-L-homo-
serine lactone regulates carbapenem antibiotic production in Erwinia caro-
tovora. Biochem. J. 288:997–1004.
5. Barber, C. E., J. L. Tang, J. X. Fend, M. Q. Pan, T. J. G. Wilson, H. Slater,
J. M. Dow, P. Williams, and M. J. Daniels. 1997. A novel regulatory system
required for pathogenicity of Xanthomonas campestris is mediated by a
small diffusible signal molecule. Mol. Microbiol. 24:555–566.
6. Barras, F., F. van Gijsegem, and A. K. Chatterjee. 1994. Extracellular
enzymes and pathogenesis of soft-rot Erwinia. Annu. Rev. Phytopathol.
7. Bassler, B. L., M. Wright, R. E. Showalter, and M. R. Silverman. 1993.
Intercellular signalling in Vibrio harveyi: sequence and function of genes
regulating expression of luminescence. Mol. Microbiol. 9:773–786.
8. Bassler, B. L., M. Wright, and M. R. Silverman. 1994. Multiple signalling
systems controlling expression of luminescence in Vibrio harveyi: sequence
and function of genes encoding a second sensory pathway. Mol. Microbiol.
9. Beck von Bodman, S., and S. K. Farrand. 1995. Capsular polysaccharide
biosynthesis and pathogenicity in Erwinia stewartii require induction by a
N-acyl-homoserine lactone autoinducer. J. Bacteriol. 177:5000–5008.
10. Beck von Bodman, S., G. T. Hayman, and S. K. Farrand. 1992. Opine
catabolism and conjugal transfer of the nopaline Ti plasmid pTiC58 are
coordinately regulated by a single repressor. Proc. Natl. Acad. Sci. USA
11. Brewer, S. C., R. G. Wunderink, C. B. Jones, and K. V. J. Leeper. 1996.
Ventilator-associated pneumonia due to Pseudomonas aeruginosa. Chest
12. Brint, J. M., and D. E. Ohman. 1995. 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. 177:7155–7163.
13. Cao, J., and E. A. Meighen. 1989. Purification and structural identification
of an autoinducer for the luminescence system of Vibrio harveyi. J. Biol.
14. Chapon-Herve, V., M. Akrim, A. Latifi, P. Williams, A. Lazdunski, and M.
Bally. 1997. Regulation of the xcp secretion pathway by multiple quorum-
sensing modulons in Pseudomonas aeruginosa. Mol. Microbiol. 24:1169–
15. Cheung, A. L., J. M. Koomey, C. A. Butler, S. J. Projan, and V. A. Fischetti.
1992. Regulation of exoprotein expression in Staphylococcus aureus by a
locus (sar) distinct from agr. Proc. Natl. Acad. Sci. USA 89:6462–6466.
16. Chhabra, S. R., P. Stead, N. J. Bainton, G. P. C. Salmond, G. S. A. B.
Stewart, P. Williams, and B. W. Bycroft. 1993. Autoregulation of carbap-
enem biosynthesis in Erwinia carotovora ATCC 39048 by analogues of
N-3-(oxohexanoyl)-L-homoserine lactone. J. Antibiot. 46:441–454.
17. Costerton, J. W., P. S. Stewart, and E. P. Greenberg. 1999. Bacterial
biofilms: a common cause of persistant infections. Science 284:1318–1322.
18. Cubo, M. T., A. Economou, G. Murphy, A. W. B. Johnston, and J. A.
Downie. 1992. Molecular characterization and regulation of the rhizos-
phere-expressed genes rhiABCR that can influence nodulation by Rhizo-
4846 MINIREVIEWINFECT. IMMUN.
bium leguminosarum biovar viciae. J. Bacteriol. 174:4026–4035.
19. Davies, D. G., M. R. Parsek, J. P. Pearson, B. H. Iglewski, J. W. Costerton,
and E. P. Greenberg. 1997. The involvement of cell-to-cell signals in the
development of a bacterial biofilm. Science 280:295–298.
20. de Kievit, T. R., P. C. Seed, L. Passador, J. Nezezon, and B. H. Iglewski.
1999. RsaL, a novel repressor of virulence gene expression in Pseudomonas
aeruginosa. J. Bacteriol. 181:2175–2184.
21. DiMango, E., H. J. Zar, R. Bryan, and A. Prince. 1995. Diverse Pseudomo-
nas aeruginosa gene products stimulate respiratory epithelial cells to pro-
duce interleukin-8. J. Clin. Investig. 96:2204–2210.
22. Dong, Y.-H., J.-L. Xu, X.-Z. Li, and L.-H. Zhang. 2000. AiiA, an enzyme
that inactivates the acylhomoserine lactone quorum-sensing signal and at-
tenuates the virulence of Erwinia carotovora. Proc. Natl. Acad. Sci. USA
23. Dunn, M., and R. G. Wunderink. 1995. Ventilator-associated pneumonia
caused by Pseudomonas infection. Clinics Chest Med. 16:95–109.
24. Dunny, G. M., H. Hirt, and S. Erlandsen. 1999. Multiple roles for entero-
coccal sex pheromone peptides in conjugation, plasmid maintenance and
pathogenesis, p. 117–138. In R. England, G. Hobbs, N. Bainton, and D. M.
Roberts (ed.), Microbial signalling and communication. University Press,
Cambridge, United Kingdom.
25. Dunny, G. M., and B. A. B. Leonard. 1997. Cell-cell communication in
Gram-positive bacteria. Annu. Rev. Microbiol. 51:527–564.
26. Eberhard, A., A. L. Burlingame, C. Eberhard, G. L. Kenyon, K. H. Nealson,
and J. Oppenheimer. 1981. Structural identification of autoinducer of Pho-
tobacterium fischeri luciferase. Biochemistry 20:2444–2449.
27. Eberl, L., M. K. Winson, C. Sternberg, G. S. A. B. Stewart, G. Christiansen,
S. R. Chhabra, B. W. Bycroft, P. Williams, S. Molin, and M. Givskov. 1996.
Involvement of N-acyl-L-homoserine lactone autoinducers in controlling
the multicellular behavior of Serratia liquifaciens. Mol. Microbiol. 20:127–
28. Elliott, S. J., L. A. Wainwright, T. K. McDaniel, K. G. Jarvis, Y. K. Deng,
L. C. Lai, B. P. McNamara, M. S. Donnenberg, and J. B. Kaper. 1998. The
complete sequence of the locus of enterocyte effacement (LEE) from en-
teropathogenic Escherichia coli E2348/69. Mol. Microbiol. 28:1–4.
29. Ellis, J. G., A. Kerr, A. Petit, and J. Tempe ´. 1982. Conjugal transfer of
nopaline and agropine Ti-plasmids—the role of agrocinopines. Mol. Gen.
30. Engebrecht, J., K. H. Nealson, and M. Silverman. 1983. Bacterial biolumi-
nescence: isolation and genetic analysis of the functions from Vibrio fischeri.
31. Engebrecht, J., and M. Silverman. 1987. Nucleotide sequence of the reg-
ulatory locus controlling expression of bacterial genes for bioluminescence.
Nucleic Acids Res. 15:10455–10467.
32. Farrand, S. K., I. Hwang, and D. M. Cook. 1996. The tra region of the
nopaline-type Ti plasmid is a chimera with elements related to the transfer
systems of RSF1010, RP4, and F. J. Bacteriol. 178:4233–4247.
33. Fergie, J. E., S. J. Shema, L. Lott, R. Crawford, and C. C. Patrick. 1994.
Pseudomonas aeruginosa bacteremia in immunocompromised children:
analysis of factors associated with a poor outcome. Clin. Infect. Dis. 18:
34. Flavier, A. B., S. J. Clough, M. A. Schell, and T. P. Denny. 1997. Identifi-
cation of 3-hydroxypalmitic acid methyl ester as a novel autoregulator
controlling virulence in Ralstonia solanacearum. Mol. Microbiol. 26:251–
35. Flavier, A. B., L. M. Ganova-Raeva, M. A. Schell, and T. P. Denny. 1997.
Hierarchical autoinduction in Ralstonia solanacearum: control of acyl-ho-
moserine lactone production by a novel autoregulatory system responsive to
3-hydroxypalmitic acid ester. J. Bacteriol. 179:7089–7097.
36. Fray, R. G., J. P. Throup, M. Daykin, A. Wallace, P. Williams, G. S. A. B.
Stewart, and D. Grierson. 1999. Plants genetically modified to produce
N-acylhomoserine lactones communicate with bacteria. Nat. Biotechnol.
37. Fuqua, C., and A. Eberhard. 1999. Signal generation in autoinduction
systems: synthesis of acylated homoserine lactones by LuxI-type proteins, p.
211–230. In G. M. Dunny and S. C. Winans (ed.), Cell-cell signaling in
bacteria. ASM Press, Washington, D.C.
38. Fuqua, C., and S. C. Winans. 1996. Localization of OccR-activated and
TraR-activated promoters that express two ABC-type permeases and the
traR gene of Ti plasmid pTiR10. Mol. Microbiol. 20:1199–1210.
39. Fuqua, W. C., S. C. Winans, and E. P. Greenberg. 1994. Quorum sensing in
bacteria: the LuxR/LuxI family of cell density-responsive transcriptional
regulators. J. Bacteriol. 176:269–275.
40. Fuqua, W. C., S. C. Winans, and E. P. Greenberg. 1996. Census and
consensus in bacterial ecosystems: the LuxR-LuxI family of quorum-sensing
transcriptional regulators. Annu. Rev. Microbiol. 50:727–751.
41. Gamard, P., F. Sauriol, N. Benhamou, R. R. Belanger, and T. C. Paulitz.
1997. Novel butyrolactones with antifungal activity produced by Pseudomo-
nas aureofaciens strain 63-28. J. Antibiot. 50:742–749.
42. Gambello, M. J., and B. H. Iglewski. 1991. Cloning and characterization of
the Pseudomonas aeruginosa lasR gene: a transcriptional activator of elas-
tase expression. J. Bacteriol. 173:3000–3009.
43. Gambello, M. J., S. Kaye, and B. H. Iglewski. 1993. LasR of Pseudomonas
aeruginosa is a transcriptional activator of the alkaline protease gene (apr)
and an enhancer of exotoxin A expression. Infect. Immun. 61:1180–1184.
44. Givskov, M., L. Eberl, and S. Molin. 1997. Control of exoenzyme produc-
tion, motility and cell differentiation in Serratia liquifaciens. FEMS Micro-
biol. Lett. 148:115–122.
45. Givskov, M., R. de Nys, M. Manefield, L. Gram, R. Maximilien, L. Eberl,
S. Molin, P. D. Steinberg, and S. Kjelleberg. 1996. Eukaryotic interference
with homoserine lactone-mediated prokaryotic signalling. J. Bacteriol. 178:
46. Govan, J. R. W., J. E. Hughes, and P. Vandamme. 1996. Burkholderia
cepacia: medical, taxonomic and ecological issues. J. Med. Microbiol. 45:
47. Gray, K. M., J. P. Pearson, J. A. Downie, B. E. A. Boboye, and E. P.
Greenberg. 1996. Cell-to-cell signaling in the symbiotic nitrogen-fixing bac-
terium Rhizobium leguminosarum: autoinduction of stationary phase and
rhizosphere-expressed genes. J. Bacteriol. 178:372–376.
48. Hanzelka, B. L., and E. P. Greenberg. 1996. Quorum sensing in Vibrio
fischeri: evidence that S-adenosyl methionine is the amino acid substrate for
autoinducer synthesis. J. Bacteriol. 178:5291–5294.
49. Holden, M. T. G., S. R. Chhabra, R. de Nys, P. Stead, N. J. Bainton, P. J.
Hill, M. Manefield, N. Kumar, M. Labatte, D. England, S. Rice, M. Givs-
kov, G. P. C. Salmond, G. S. A. B. Stewart, B. W. Bycroft, S. Kjelleberg, and
P. Williams. 1999. Quorum-sensing cross talk: isolation and chemical char-
acterization of cyclic dipeptides from Pseudomonas aeruginosa and other
Gram-negative bacteria. Mol. Microbiol. 33:1254–1266.
50. Hwang, I., D. M. Cook, and S. K. Farrand. 1995. A new regulatory element
modulates homoserine lactone-mediated autoinduction of Ti plasmid con-
jugal transfer. J. Bacteriol. 177:449–458.
51. Hwang, I., L. Pei-Li, L. Zhang, K. R. Piper, D. M. Cook, M. E. Tate, and
S. K. Farrand. 1994. TraI, a LuxI homolog, is responsible for production of
conjugation factor, the Ti plasmid N-acylhomoserine lactone autoinducer.
Proc. Natl. Acad. Sci. USA 91:4639–4643.
52. Ji, G., R. C. Beavis, and R. P. Novick. 1995. Cell density control of staph-
ylococcal virulence mediated by an octapeptide pheromone. Proc. Natl.
Acad. Sci. USA 92:12055–12059.
53. Ji, G., R. Beavis, and R. P. Novick. 1997. Bacterial interference caused by
autoinducing peptide variants. Science 276:2027–2030.
54. Jiang, Y., M. Camara, S. R. Chhabra, K. R. Hardie, B. W. Bycroft, A.
Lazdunski, G. P. C. Salmond, G. S. A. B. Stewart, and P. Williams. 1998.
In vitro biosynthesis of the Pseudomonas aeruginosa quorum-sensing signal
molecule, N-butanoyl-L-homoserine lactone. Mol. Microbiol. 28:193–204.
55. Jones, S., B. Yu, N. J. Bainton, M. Birdsall, B. W. Bycroft, S. R. Chhabra,
A. J. R. Cox, P. Golby, P. J. Reeves, S. Stephens, M. K. Winson, G. P. C.
Salmond, G. S. A. B. Stewart, and P. Williams. 1993. The lux autoinducer
regulates the production of exoenzyme virulence determinants in Erwinia
carotovora and Pseudomonas aeruginosa. EMBO J. 12:2477–2482.
56. Klapwijk, P. M., T. Scheulderman, and R. Schilperoort. 1978. Coordinated
regulation of octopine degradation and conjugative transfer of Ti plasmids
in Agrobacterium tumefaciens: evidence for a common regulatory gene and
separate operons. J. Bacteriol. 136:775–785.
57. Kleerebezem, M., L. E. N. Quadri, O. P. Kuipers, and W. M. de Vos. 1997.
Quorum sensing by peptide pheromones and two component signal trans-
duction systems in Gram-positive bacteria. Mol. Microbiol. 24:895–904.
58. Kohler, T., M. Michea-Hamzehpour, U. Henze, N. Gotoh, L. K. Curty, and
J. C. Pechere. 1997. Characterization of MexE-MexF-OprN, a positively
regulated multidrug efflux system of Pseudomonas aeruginosa. Mol. Micro-
59. Kuo, A., N. S. M. Callahan, and P. V. Dunlap. 1996. Modulation of lumi-
nescence operon expression by N-octanoyl-L-homoserine lactone in ainS
mutants of Vibrio fischeri. J. Bacteriol. 178:971–976.
60. Latifi, A., M. Foglino, K. Tanaka, P. Williams, and A. Lazdunski. 1996. A
hierarchical quorum-sensing cascade in Pseudomonas aeruginosa links the
transcriptional activators LasR and RhlR to expression of the stationary-
phase sigma factor RpoS. Mol. Microbiol. 21:1137–1146.
61. Latifi, A., M. K. Winson, M. Foglino, B. W. Bycroft, G. S. A. B. Stewart, L.
Lazdunski, and P. Williams. 1995. Multiple homologues of LuxR and LuxI
control expression of virulence determinants and secondary metabolites
through quorum sensing in Pseudomonas aeruginosa PAO1. Mol. Micro-
62. Lewenza, S., B. Conway, E. P. Greenberg, and P. A. Sokol. 1999. Quorum
sensing in Burkholderia cepacia: identification of the LuxRI homologs Ce-
pRI. J. Bacteriol. 181:748–756.
63. Lina, G., S. Jarraud, G. Ji, T. Greenland, A. Pedraza, J. Etienne, R. P.
Novick, and F. Vandenesch. 1998. Transmembrane topology and histidine
protein kinase activity of AgrC, the agr signal receptor in Staphylococcus
aureus. Mol. Microbiol. 28:655–662.
64. McDaniel, T. K., K. G. Jarvis, M. S. Donnenberg, and J. B. Kaper. 1995. A
genetic locus of enterocyte effacement conserved among diverse enterobac-
terial pathogens. Proc. Natl. Acad. Sci. USA 92:1664–1668.
65. McGowan, S., M. Sebaihia, S. Jones, S. Yu, N. Bainton, P. F. Chan, B. W.
Bycroft, G. S. A. B. Stewart, G. P. C. Salmond, and P. Williams. 1995.
VOL. 68, 2000 MINIREVIEW4847
Carbapenem antibiotic production in Erwinia carotovora is regulated by
CarR, a homologue of the LuxR transcriptional activator. Microbiology
66. McKenney, D., K. E. Brown, and D. G. Allison. 1995. Influence of Pseudo-
monas aeruginosa exoproducts on virulence factor production in Burkhold-
eria cepacia: evidence of interspecies communication. J. Bacteriol. 177:
67. McLean, K. H., M. K. Winson, L. Fish, A. Taylor, S. R. Chhabra, M.
Camara, M. Daykin, J. H. Lamb, S. Swift, B. W. Bycroft, G. S. A. B. Stewart,
and P. Williams. 1997. Quorum sensing and Chromobacterium violaceum:
exploitation of violacein production and inhibition for the detection of
N-acylhomoserine lactones. Microbiology 143:3703–3711.
68. Mendelson, M. H., A. Gurtman, S. Szabo, E. Neibart, B. R. Meyers, M.
Policar, T. W. Cheung, D. Lillienfeld, G. Hammer, S. Reddy, K. Choi, and
S. Z. Hirschman. 1994. Pseudomonas aeruginosa bacteremia in patients with
AIDS. Clin. Infect. Dis. 18:886–895.
69. Milton, D. L., A. Hardman, M. Camara, S. R. Chhabra, B. W. Bycroft,
G. S. A. B. Stewart, and P. Williams. 1997. Quorum sensing in Vibrio
anguillarum: characterization of the vanI/vanR locus and identification of
the autoinducer N-(3-oxododecanoyl)-L-homoserine lactone. J. Bacteriol.
70. More ´, M. I., L. D. Finger, J. L. Stryker, C. Fuqua, A. Eberhard, and S. C.
Winans. 1996. Enzymatic synthesis of a quorum-sensing autoinducer
through use of defined substrates. Science 272:1655–1658.
71. Morfeldt, E., L. Janzon, S. Arvidson, and S. Lofdahl. 1988. Cloning of a
chromosomal locus (exp) which regulates the expression of several exopro-
tein genes in Staphylococcus aureus. Mol. Gen. Genet. 211:435–440.
72. Nasser, W., M. L. Bouillant, G. Salmond, and S. Reverchon. 1998. Char-
acterization of the Erwinia chrysanthemi expI-expR locus directing the syn-
thesis of two N-acyl-homoserine lactone signal molecules. Mol. Microbiol.
73. Ochsner, U. A., A. K. Koch, A. Fiechter, and J. Reiser. 1994. Isolation and
characterization of a regulatory gene affecting rhamnolipid biosurfactant
synthesis in Pseudomonas aeruginosa. J. Bacteriol. 176:2044–2054.
74. Ochsner, U. A., and J. Reiser. 1995. Autoinducer-mediated regulation of
rhamnolipid biosurfactant synthesis in Pseudomonas aeruginosa. Proc. Natl.
Acad. Sci. USA 92:6424–6428.
75. Palva, T. K., M. Hurtig, P. Saindrenan, and E. T. Palva. 1994. Salicylic acid
induced resistance to Erwinia carotovora subsp. carotovora in tobacco. Mol.
Plant-Microbe Interact. 7:356–363.
76. Passador, L., J. M. Cook, M. J. Gambello, L. Rust, and B. H. Iglewski. 1993.
Expression of Pseudomonas aeruginosa virulence genes requires cell-to-cell
communication. Science 260:1127–1130.
77. Pearson, J. P., M. Feldman, B. H. Iglewski, and A. Prince. 2000. Pseudo-
monas aeruginosa cell-to-cell signaling is required for virulence in a model
of acute pulmonary infection. Infect. Immun. 68:4331–4334.
78. Pearson, J. P., K. M. Gray, L. Passador, K. D. Tucker, A. Eberhard, B. H.
Iglewski, and E. P. Greenberg. 1994. Structure of the autoinducer required
for expression of Pseudomonas aeruginosa virulence genes. Proc. Natl.
Acad. Sci. USA 91:197–201.
79. Pearson, J. P., L. Passador, B. H. Iglewski, and E. P. Greenberg. 1995. A
second N-acylhomoserine lactone signal produced by Pseudomonas aerugi-
nosa. Proc. Natl. Acad. Sci. USA 92:1490–1494.
80. Pearson, J. P., E. C. Pesci, and B. H. Iglewski. 1997. Roles of Pseudomonas
aeruginosa las and rhl quorum-sensing systems in control of elastase and
rhamnolipid biosynthesis genes. J. Bacteriol. 179:5756–5767.
81. Pearson, J. P., C. Van Delden, and B. H. Iglewski. 1999. Active efflux and
diffusion are involved in transport of Pseudomonas aeruginosa cell-to-cell
signals. J. Bacteriol. 181:1203–1210.
82. Pesci, E. C., J. B. Milbank, J. P. Pearson, S. McKnight, A. S. Kende, E. P.
Greenberg, and B. H. Iglewski. 1999. Quinolone signaling in the cell-to-cell
communication system of Pseudomonas aeruginosa. Proc. Natl. Acad. Sci.
83. Pesci, E. C., J. P. Pearson, P. C. Seed, and B. H. Iglewski. 1997. Regulation
of las and rhl quorum sensing in Pseudomonas aeruginosa. J. Bacteriol.
84. Pierson, L. S., III, V. D. Keppenne, and D. W. Wood. 1994. Phenazine
antibiotic biosynthesis in Pseudomonas aureofaciens 30-84 is regulated by
PhzR in response to cell density. J. Bacteriol. 176:3966–3974.
85. Pierson, L. S., III, and L. S. Thomashow. 1992. Cloning and heterologous
expression of the phenazine biosynthetic locus of Pseudomonas aureofaciens
30-84. Mol. Plant-Microbe Interact. 5:330–339.
86. Pierson, L. S., III, D. W. Wood, and S. Beck von Bodman. 1999. Quorum
sensing in plant-associated bacteria, p. 101–116. In G. M. Dunny, and S. C.
Winans (ed.), Cell-cell signaling in bacteria. ASM Press, Washington, D.C.
87. Piper, K. R., S. Beck von Bodman, and S. K. Farrand. 1993. Conjugation
factor of Agrobacterium tumefaciens regulates Ti plasmid transfer by auto-
induction. Nature 362:448–450.
88. Pirhonen, M., D. Flego, R. Heikinheimo, and E. T. Palva. 1993. A small
diffusible signal molecule is responsible for the global control of virulence
and exoenzyme production in the plant pathogen Erwinia carotovora.
EMBO J. 12:2467–2476.
89. Poole, K., N. Gotoh, H. Tsujimoto, Q. Zhao, A. Wada, T. Yamasaki, S.
Neshat, J. Yamagishi, X. Z. Li, and T. Nishino. 1996. Overexpression of the
mexC-mexC-oprJ efflux operon in nfxB-type multidrug-resistant strains of
Pseudomonas aeruginosa. Mol. Microbiol. 21:713–724.
90. Poole, K., K. Krebes, C. McNally, and S. Neshat. 1993. Multiple antibiotic
resistance in Pseudomonas aeruginosa: evidence for involvement of an efflux
operon. J. Bacteriol. 175:7363–7372.
91. Prasad, C. 1995. Bioactive cyclic dipeptides. Peptides 16:151–164.
92. Puskas, A., E. P. Greenberg, S. Kaplan, and A. L. Schaefer. 1997. A
quorum-sensing system in the free-living photosynthetic bacterium
Rhodobacter sphaerhoides. J. Bacteriol. 179:7530–7537.
93. Rahme, L. G., E. J. Stevens, S. F. Wolfort, J. Shao, R. G. Tompkins, and
F. M. Ausubel. 1995. Common virulence factors for bacterial pathogenicity
in plants and animals. Science 268:1899–1902.
94. Rahme, L. G., M.-W. Tan, L. Le, S. M. Wong, R. G. Tompkins, S. B.
Calderwood, and F. M. Ausubel. 1997. Use of model plant hosts to identify
Pseudomonas aeruginosa virulence factors. Proc. Natl. Acad. Sci. USA 94:
95. Rechtin, T. M., A. F. Gillaspy, M. A. Schumacher, R. G. Brennan, M. S.
Smeltzer, and B. K. Hurlburt. 1999. Characterization of the SarA virulence
gene regulator of Staphylococcus aureus. Mol. Microbiol. 33:307–316.
96. Recsei, P., B. Kreiswirth, M. O’Reilly, P. Schlievert, A. Gruss, and R. P.
Novick. 1986. Regulation of exoprotein gene expression in Staphylococcus
aureus by agr. Mol. Gen. Genet. 202:58–61.
97. Reimmann, C., M. Beyeler, A. Latifi, H. Winteler, M. Foglino, A. Lazdun-
ski, and D. Haas. 1997. The global activator GacA of Pseudomonas aerugi-
nosa PAO positively controls the production of the autoinducer N-butyryl-
homoserine lactone and the formation of the virulence factors pyocyanin,
cyanide, and lipase. Mol. Microbiol. 24:309–319.
98. Reverchon, S., M. L. Bouillant, G. Salmond, and W. Nasser. 1998. Integra-
tion of the quorum-sensing system in the regulatory networks controlling
virulence factor synthesis in Erwinia chrysanthemi. Mol. Microbiol. 29:1407–
99. Rodelas, B., J. K. Lithgow, F. Wisniewski-Dye, A. Hardman, A. Wilkinson,
A. Economou, P. Williams, and J. A. Downie. 1999. Analysis of quorum-
sensing-dependent control of rhizosphere-expressed (rhi) genes in Rhizo-
bium leguminosarum bv. viciae. J. Bacteriol. 181:3816–3823.
100. Rosemeyeer, V., J. Michiels, C. Verreth, and J. Vanderleyden. 1998. luxI-
and luxR-homologous genes of Rhizobium etli CNPAF512 contribute to
synthesis of autoinducer molecules and nodulation of Phaseolus vulgaris. J.
101. Rumbaugh, K. P., J. A. Griswold, and A. N. Hamood. 1999. Contribution of
the regulatory gene lasR to the pathogenesis of Pseudomonas aeruginosa
infection of burned mice. J. Burn Care Rehabil. 20:42–49.
102. Rumbaugh, K. P., J. A. Griswold, B. H. Iglewski, and A. N. Hamood. 1999.
Contribution of quorum sensing to the virulence of Pseudomonas aerugi-
nosa in burn wound infections. Infect. Immun. 67:5854–5862.
103. Schaefer, A. L., B. L. Hanzelka, A. Eberhard, and E. P. Greenberg. 1996.
Quorum sensing in Vibrio fischeri: probing autoinducer-LuxR interactions
with autoinducer analogs. J. Bacteriol. 178:2897–2901.
104. Schaefer, A. L., D. L. Val, B. L. Hanzelka, J. E. Cronan, and E. P. Green-
berg. 1996. Generation of cell-to-cell signals in quorum sensing: acylhomo-
serine synthase activity of a purified Vibrio fischeri LuxI protein. Proc. Natl.
Acad. Sci. USA 93:9505–9509.
105. Schripsema, J., K. E. E. de Rudder, T. B. van Vliet, P. P. Lankhorst, E. de
Vroom, J. W. Kijne, and A. A. N. van Brussel. 1996. Bacteriocin small of
Rhizobium leguminosarum belongs to the class of N-acyl-L-homoserine lac-
tone molecules, known as autoinducers and as quorum sensing co-tran-
scriptional factors. J. Bacteriol. 178:366–371.
106. Seed, P. C., L. Passador, and B. H. Iglewski. 1995. Activation of the
Pseudomonas aeruginosa lasI gene by LasR and the Pseudomonas autoin-
ducer PAI: an autoinduction regulatory hierarchy. J. Bacteriol. 177:654–
107. Sharma, S., T. F. Stark, W. G. Beattie, and R. E. Moses. 1986. Multiple
control elements for the uvrC gene unit of Escherichia coli. Nucleic Acids
108. Showalter, R. E., M. O. Martin, and M. R. Silverman. 1990. Cloning and
nucleotide sequence of luxR, a regulatory gene controlling luminescence in
Vibrio harveyi. J. Bacteriol. 172:2946–2954.
109. Sitnikov, D. M., J. B. Schineller, and T. O. Baldwin. 1995. Transcriptional
regulation of bioluminescence genes from Vibrio fischeri. Mol. Microbiol.
110. Sperandio, V., J. L. Mellies, W. Nguyen, S. Shin, and J. B. Kaper. 1999.
Quorum sensing controls expression of the type III secretion gene tran-
scription and protein secretion in enterohemorrhagic and enteropathogenic
Escherichia coli. Proc. Natl. Acad. Sci. USA 96:15196–15201.
111. Storey, D. G., E. E. Ujack, H. R. Rabin, and I. Mitchell. 1998. Pseudomonas
aeruginosa lasR transcription correlates with the transcription of lasA, lasB,
and toxA in chronic lung infections associated with cystic fibrosis. Infect.
112. Surette, M. G., and B. L. Bassler. 1998. Quorum sensing in Escherichia coli
and Salmonella typhimurium. Proc. Natl. Acad. Sci. USA 95:7046–7050.
4848 MINIREVIEWINFECT. IMMUN.
113. Surette, M. G., M. B. Miller, and B. L. Bassler. 1999. Quorum sensing in Download full-text
Escherichia coli, Salmonella typhimurium and Vibrio harveyi: a new family of
genes responsible for autoinducer production. Proc. Natl. Acad. Sci. USA
114. Swift, S., A. V. Karlyshev, E. L. Durant, M. K. Winson, S. R. Chhabra, P.
Williams, S. Macintyre, and G. S. A. B. Stewart. 1997. Quorum sensing in
Aeromonas hydrophila and Aeromonas salmonicida: identification of the
LuxRI homologues AhyRI and AsaRI and their cognate signal molecules.
J. Bacteriol. 179:5271–5281.
115. Swift, S., M. K. Winson, P. F. Chan, N. J. Bainton, M. Birdsall, P. J. Reeves,
C. E. D. Rees, S. R. Chhabra, P. J. Hill, J. P. Throup, B. W. Bycroft, G. P. C.
Salmond, P. Williams, and G. S. A. B. Stewart. 1993. A novel strategy for
the isolation of luxI homologues: evidence for the widespread distribution
of a LuxR:LuxI superfamily in enteric bacteria. Mol. Microbiol. 10:511–520.
116. Tan, M.-W., L. G. Rahme, J. A. Sternberg, R. G. Tompkins, and F. M.
Ausubel. 1999. Pseudomonas aeruginosa killing of Caenorhabditis elegans
used to identify P. aeruginosa virulence factors. Proc. Natl. Acad. Sci. USA
117. Tang, H. B., E. DiMango, R. Bryan, M. Gambello, B. H. Iglewski, J. B.
Goldberg, and A. Prince. 1996. Contribution of specific Pseudomonas
aeruginosa virulence factors to pathogenesis of pneumonia in a neonatal
mouse model of infection. Infect. Immun. 64:37–43.
118. Taylor, R. F. H., H. Gaya, and M. E. Hodson. 1993. Pseudomonas cepacia:
pulmonary infection in patients with cystic fibrosis. Respir. Med. 87:187–
119. Telford, G., D. Wheeler, P. Williams, P. T. Tomkins, P. Appleby, H. Sewell,
G. S. A. B. Stewart, B. W. Bycroft, and D. I. Pritchard. 1998. The Pseudo-
monas aeruginosa quorum-sensing signal molecule N-(3-oxododecanoyl)-L-
homoserine lactone has immunomodulatory activity. Infect. Immun. 66:36–
120. Throup, J. P., M. Camara, G. S. Briggs, M. K. Winson, S. R. Chhabra,
B. W. Bycroft, P. Williams, and G. S. A. B. Stewart. 1995. Characterisation
of the yenI/R locus from Yersinia enterocolitica mediating the synthesis of
two N-acyl-homoserine lactone signal molecules. Mol. Microbiol. 17:345–
121. Toder, D. S., M. J. Gambello, and B. H. Iglewski. 1991. Pseudomonas
aeruginosa LasA: a second elastase gene under transcriptional control of
lasR. Mol. Microbiol. 5:2003–2010.
122. Van Delden, C., E. C. Pesci, J. P. Pearson, and B. H. Iglewski. 1998.
Starvation selection restores elastase and rhamnolipid production in a
Pseudomonas aeruginosa quorum-sensing mutant. Infect. Immun. 66:4499–
123. Whooley, M. A., and A. McLoughlin. 1983. The proton motive force in
Pseudomonas aeruginosa and its relationship to exoprotease production.
J. Gen. Microbiol. 129:989–996.
124. Whooley, M. A., J. A. O’Callaghan, and A. J. McLoughlin. 1983. Effect of
substrate on the regulation of exoprotease production by Pseudomonas
aeruginosa ATCC 10145. J. Gen. Microbiol. 129:981–988.
125. Winans, S. C., J. Zhu, and M. I. More ´. 1999. Cell density-dependent gene
expression by Agrobacterium tumefaciens during colonization of crown gall
tumors, p. 117–128. In G. M. Dunny and S. C. Winans (ed.), Cell-cell
signaling in bacteria. ASM Press, Washington, D.C.
126. Winson, M. K., M. Camara, A. Latifi, M. Foglino, S. R. Chhabra, M.
Daykin, M. Bally, V. Chapon, G. P. C. Salmond, B. W. Bycroft, A. Lazdun-
ski, G. S. A. B. Stewart, and P. Williams. 1995. Multiple N-acyl-L-homo-
serine lactone signal molecules regulate production of virulence determi-
nants and secondary metabolites in Pseudomonas aeruginosa. Proc. Natl.
Acad. Sci. USA 92:9427–9431.
127. Withers, H. L., and K. Nordstrom. 1998. Quorum-sensing acts at initiation
of chromosomal replication in Escherichia coli. Proc. Natl. Acad. Sci. USA
128. Wood, D. W., and L. S. Pierson III. 1996. The phzI gene of Pseudomonas
aureofaciens 30-84 is responsible for the production of a diffusible signal
required for phenazine antibiotic production. Gene 168:49–53.
129. Zhang, L., and A. Kerr. 1991. A diffusible compound can enhance conjugal
transfer of the Ti plasmid in Agrobacterium tumefaciens. J. Bacteriol. 173:
130. Zhang, L., P. J. Murphy, A. Kerr, and M. E. Tate. 1993. Agrobacterium
conjugation and gene regulation by N-acyl-L-homoserine lactones. Nature
131. Zhu, J., J. W. Beaber, M. I. More ´, C. Fuqua, A. Eberhard, and S. C.
Winans. 1998. Analogs of the autoinducer 3-oxooctanoyl-homoserine lac-
tone strongly inhibit activity of the TraR protein of Agrobacterium tumefa-
ciens. J. Bacteriol. 180:5398–5405.
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