Quorum Sensing, Bacteria Talk Sense

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Quorum Sensing: Bacteria Talk Sense
Cell communication in bacteria occurs through a vernacular of small diffusible
chemical signals that impact gene regulation during times of high cell density. This
form of intercellular signaling, known as quorum sensing, optimizes the metabolic
and behavioral activities of a community of bacteria for life in close quarters.
Quorum sensing is best characterized as a means of communication within a
bacterial species, whereas competitive or cooperative signaling can occur between
groups of bacteria or between bacteria and the host. These systems are often
integrated into complex, multilayered signal transduction networks that control
numerous multicellular behaviors, including biofilm formation and other virulence
traits. In addition, quorum signals, sensors, and signaling pathways are
increasingly recognized as having biological properties that extend beyond cell
communication. The deeper understanding of microbial cell communication
promises to shed light on the complexities of the host-microbe relationship and
may lead to novel therapeutic applications.
Cell communication and signaling are essential for the proper growth and
development of all living multicellular organisms. Because of its universal
importance, it is not surprising that many fundamental aspects of cell
communication have been evolutionarily conserved between plants, animals, and
unicellular eukaryotes, even though these kingdoms diverged more than 1 billion
years ago .
Cell communication in bacteria and in some eukaryotic microorganisms occurs in a
population-density dependent manner and is based on the production of and
response to small pheromone-like biochemical molecules called autoinducers.
Differential gene regulation in response to intercellular signaling provides
microbes with a means to express particular behaviors only while growing in social
communities. This process has been termed quorum sensing to reflect the need for
a sufficient population of microbes (and concentration of signal) to activate the
system .
Types of Autoinducers
Microbially derived signalling molecules act as auto inducers in bacterial quorum
sensing. The Gram-negative bacteria use fatty acid derivatives called Homoserine

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Lactones HSLs whose synthesis is dependent on LuxI homolog or LuxR homolog
encoding a transcriptional activator protein responsible for detection of the cognate
HSL and the resulting gene expression which results in phenotypic changes. More
than 30 species of Gram-negative bacteria use HSL derivatives for the control of
the cell density and hence the quorum sensing phenomenon.
The Gram-positive bacteria use amino acids and short peptide derivatives for
quorum sensing.
(1) Acyl Homoserine Lactone molecules
The AHL signal molecules from different bacteria are related in structure, but
differ in the nature of the acyl side chain moieties attached to them.The acyl group
can vary from 4 to 14 carbons depending on the auto inducer. It also possesses a
hydroxyl group, a carbonyl group, it is either fully saturated or contains a single
carbon-carbon double bond. A significant number of microbial acyl HSLs have
even number of carbons in their acyl side chains and are synthesized by different
bacterial genera. Many bacterial species can produce more than one type of Acyl
Homoserine Lactone and the type of acyl HSL produced by a particular species can
be strain dependent.
(2) Synthesis of Autoinducers
The Homoserines found in bacteria are intermediates of the methionine-lysine-
threonine bio synthetic pathway. S-adenosylmethionine (SAM) is one of the
intermediates of methionine/homocysteine pathway.

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Gram-Negative Bacteria
N>-acylhomoserine lactone (AHL) signaling.
The lux-type quorum-sensing system is the archetypal and preeminent mechanism
for species-specific communication in gram-negative bacteria . First identified in
marine Vibrio species, lux-type quorum sensing is based on the production of and
responses to AHLs. In general, lux-type systems consist of 2 components, an
autoinducer synthase (e.g., LuxI), which synthesizes AHLs from S-adenyosyl
methionine, and a transcriptional regulator (e.g., LuxR). Because of its small size
and lipophilic character, AHL freely diffuses across cell membranes. As the
population density increases, intracellular AHL binds the functionally linked
(cognate) LuxR-like receptor at a sufficient concentration within the cytoplasm to
induce differential gene expression.
Gram-Positive Bacteria
Intercellular communication is also used by gram-positive pathogens to control
virulence. Rather than using AHL or quinolone-based signaling molecules, cell
communication in gram-positive bacteria is based on the production and detection
of modified oligopeptides called autoinducing peptides (AIPs). The best-studied
system is the quorum-sensing system ofS. aureus, which is encoded by the
accessory gene regulator (agr) locus. Analogous to the function that quorum
sensing plays in P. aeruginosavirulence, the agr system is central to a complex
regulatory network that controls the production of a broad array of S.
aureus virulence factors . Moreover, agr also has a complex relationship with
biofilm formation, which has significant clinical implications.
Genetic Support of Quorum Sensing
Quorum sensing is of ancient origin in many species, although when it first arose
in the evolution of bacteria is not clear . The components of quorum-sensing
systems are typically encoded by chromosomal genes, which likely were acquired
by horizontal gene transfer . The recent discovery of a functional AHL system
within a mobile transposon in Serratia marcescens supports this hypothesis . Once
transferred to a new bacterial genome, quorum-sensing systems integrate with

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native signal-transduction systems to produce regulatory networks that are often
unique to a given species.
Quorum Sensing and Biofilm
Coincident with the elucidation of cell communication systems in bacteria has been
the growing appreciation of the importance of biofilms in bacterial physiology and
virulence. Most bacteria in the environment reside in biofilms, as do many of those
involved in human infection . Interestingly, another small-molecule signaling
system, based on the intracellular second messenger bis-(3'-5')-cyclic dimeric
guanosine monophosphate (cyclic-di-GMP), has been shown to control the ability
of flagellated bacteria, such as P. aeruginosa, to switch from planktonic to biofilm
growth . The close proximity of bacteria and limited diffusion of molecules within
the biofilm matrix suggest that quorum sensing may be crucial for the development
of biofilm-associated infections.
P. aeruginosa. The first evidence that quorum sensing may influence biofilm
formation was reported in association with P. aeruginosa, when alasI mutant was
found to produce a thinner biofilm that was more susceptible to disruption by
detergents . These findings, along with reports of the contribution of quorum
sensing to biofilm formation in other bacteria, have led to considerable interest in
the development of quorum-sensing inhibitors as a means to prevent or treat
biofilm-associated infections. In fact, recent work has shown that compounds that
inhibit quorum sensing impede biofilm formation by P. aeruginosa . It should be
noted, however, that P. aeruginosa strains that lack functional quorum-sensing
systems can, nevertheless, still cause infection .

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Quorum Sensing as a Therapeutic Target
Recently, compounds that inhibit quorum sensing have received considerable
attention as a potentially novel class of antimicrobial agents. Pharmacologic
inhibition of quorum sensing is a particularly attractive approach for the prevention
or treatment of chronic infections with high bacterial cell density or limited
diffusion environments, such as chronic lung infections in patients with cystic
fibrosis or chronic wound infections . In addition, it has been hypothesized that the
development of resistance to quorum sensing inhibitors should be limited, because
these agents would attenuate virulence but not impede bacterial growth .
Pharmacologic interference of intercellular signaling can be envisioned at several
steps in the quorum-sensing circuitry. Potential strategies include inhibiting
receptor synthesis or function, reducing production or release of functional
autoinducer, stimulating autoinducer degradation, or inhibiting autoinducer-
receptor binding. Examples of each of these mechanisms can be found in nature .
For instance, the observation that fronds of the Australian red seaweed Delisea
pulchra are rarely fouled with marine biofilms led to the discovery of a class of
halogenated furanones with quorum-sensing inhibitory activity. Structurally
similar to AHLs, these furanones appear to act as competitive inhibitors of LuxR-
type receptors . With use of natural furanones as lead compounds, synthetic
halogenated furanones with potent in vitro and in vivo anti-quorum-sensing
activity have been developed .