Editing Quorum sensing (section)

==Bacteria==
{{microbial and microbot movement|collective}}
[[File:Quorum sensing of Gram Negative cell.pdf|thumb|upright=1.2|Quorum sensing of gram-negative cell]]
[[File:Gram Positive Bacteria Quorum Sensing.pdf|thumb|upright=1.2|Gram-positive bacteria quorum sensing]]

Some of the best-known examples of quorum sensing come from studies of [[bacteria]]. Bacteria use quorum sensing to regulate certain [[phenotype]] expressions, which in turn, coordinate their behaviors. Some common phenotypes include [[biofilm]] formation, [[virulence]] factor expression, and [[motility]]. Certain bacteria are able to use quorum sensing to regulate [[bioluminescence]], [[nitrogen fixation]] and [[Spore|sporulation]].<ref name=":0">{{cite journal | vauthors = Pan J, Ren D | title = Quorum sensing inhibitors: a patent overview | journal = Expert Opinion on Therapeutic Patents | volume = 19 | issue = 11 | pages = 1581–1601 | date = November 2009 | pmid = 19732032 | doi = 10.1517/13543770903222293 | s2cid = 30007165 }}</ref>

The quorum-sensing function is based on the local density of the bacterial population in the immediate environment.<ref name="Miller Bassler 2001"/> It can occur within a single bacterial species, as well as between diverse species. Both [[gram-positive bacteria|gram-positive]] and [[gram-negative bacteria|gram-negative]] bacteria use quorum sensing, but there are some major differences in their mechanisms.<ref name=":1">{{cite journal | vauthors = Bassler BL | title = How bacteria talk to each other: regulation of gene expression by quorum sensing | journal = Current Opinion in Microbiology | volume = 2 | issue = 6 | pages = 582–587 | date = December 1999 | pmid = 10607620 | doi = 10.1016/s1369-5274(99)00025-9 }}</ref>

===Mechanism===
For the bacteria to use quorum sensing constitutively, they must possess three abilities: secretion of a signaling molecule, secretion of an [[autoinducer]] (to detect the change in concentration of signaling molecules), and regulation of gene [[Transcription (biology)|transcription]] as a response.<ref name=":0" /> This process is highly dependent on the [[diffusion]] mechanism of the signaling molecules. QS signaling molecules are usually secreted at a low level by individual bacteria. At low cell density, the molecules may just diffuse away. At high cell density, the local concentration of signaling molecules may exceed its threshold level, and trigger changes in gene expression.<ref name=":1" />

====Gram-positive bacteria====
Gram-positive bacteria use [[Autoinducer#Peptides|autoinducing peptide]]s (AIP) as their autoinducers.<ref name=":2">{{cite journal | vauthors = Rutherford ST, Bassler BL | title = Bacterial quorum sensing: its role in virulence and possibilities for its control | journal = Cold Spring Harbor Perspectives in Medicine | volume = 2 | issue = 11 | pages = a012427 | date = November 2012 | pmid = 23125205 | pmc = 3543102 | doi = 10.1101/cshperspect.a012427 }}</ref>

When gram-positive bacteria detect high concentration of AIPs in their environment, that happens by way of AIPs binding to a receptor to activate a [[kinase]]. The kinase [[phosphorylation|phosphorylates]] a [[transcription factor]], which regulates gene transcription. This is called a [[two-component regulatory system|two-component system]].

Another possible mechanism is that AIP is transported into the [[cytosol]], and binds directly to a transcription factor to initiate or inhibit transcription.<ref name=":2" />

====Gram-negative bacteria====
Gram-negative bacteria produce [[N-Acyl homoserine lactone|N-acyl homoserine lactones]] (AHL) as their signaling molecule.<ref name=":2" /> Usually AHLs do not need additional processing, and bind directly to transcription factors to regulate gene expression.<ref name=":1" />

Some gram-negative bacteria may use the two-component system as well.<ref name=":2" />

===Examples===

====''Aliivibrio fischeri''====
The bioluminescent bacterium ''[[Aliivibrio fischeri]]'' is the first organism in which QS was observed. It lives as a [[mutualism (biology)|mutualistic]] [[symbiont]] in the [[photophore]] (or light-producing organ) of the [[Hawaiian bobtail squid]]. When ''A. fischeri'' cells are free-living (or [[plankton]]ic), the autoinducer is at low concentration, and, thus, cells do not show luminescence. However, when the population reaches the threshold in the photophore (about {{10^|11}} cells/ml), transcription of [[luciferase]] is induced, leading to [[bioluminescence]].
In ''A. fischeri'', bioluminescence is regulated by AHLs (N-acyl-homoserine lactones) which is a product of the LuxI gene whose transcription is regulated by the LuxR activator. LuxR works only when AHLs binds to the LuxR.

====''Curvibacter'' sp.====
[[Curvibacter|''Curvibacter'' sp.]] is a gram-negative curved rod-formed bacterium which is the main colonizer of the epithelial cell surfaces of the early branching metazoan ''[[Hydra vulgaris]]''.<ref>{{Cite web|url=https://www.researchgate.net/publication/45278794|title=Curvibacter fontana sp. nov., a microaerobic bacteria isolated from well water|website=ResearchGate|language=en|access-date=2019-03-13}}</ref><ref name=":3">{{cite journal | vauthors = Pietschke C, Treitz C, Forêt S, Schultze A, Künzel S, Tholey A, Bosch TC, Fraune S | display-authors = 6 | title = Host modification of a bacterial quorum-sensing signal induces a phenotypic switch in bacterial symbionts | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 40 | pages = E8488–E8497 | date = October 2017 | pmid = 28923926 | pmc = 5635886 | doi = 10.1073/pnas.1706879114 | bibcode = 2017PNAS..114E8488P | doi-access = free }}</ref> Sequencing the complete [[Genome#Prokaryotic genomes|genome]] uncovered a circular chromosome (4.37 Mb), a plasmid (16.5 kb), and two [[operon]]s coding each for an AHL (N-acyl-homoserine lactone) synthase (''curI1'' and ''curI2'') and an AHL receptor (''curR1'' and ''curR2'').<ref name=":3" /> Moreover, a study showed that these host associated ''Curvibacter'' bacteria produce a broad spectrum of AHL, explaining the presence of those operons.<ref name=":3" /> As mentioned before, AHL are the quorum sensing molecules of gram-negative bacteria, which means ''Curvibacter'' has a quorum sensing activity.

Even though their function in host-microbe interaction is largely unknown, ''Curvibacter'' quorum-sensing signals are relevant for host-microbe interactions.<ref name=":3" /> Indeed, due to the [[oxidoreductase]] activity of ''Hydra'', there is a modification of AHL signalling molecules (3-oxo-homoserine lactone into 3-hydroxy-homoserine lactone) which leads to a different host-microbe interaction. On one hand, a phenotypic switch of the colonizer ''Curvibacter'' takes place. The most likely explanation is that the binding of 3-oxo-HSL and 3-hydroxy-HSL causes different conformational changes in the AHL receptors ''curR1'' and ''curR2''. As a result, there is a different DNA-binding motif affinity and thereby different target genes are activated.<ref name=":3" /> On the other hand, this switch modifies its ability to colonize the epithelial cell surfaces of ''Hydra vulgaris''.<ref name=":3" /> Indeed, one explanation is that with a 3-oxo-HSL quorum-sensing signal, there is an up-regulation of flagellar assembly. Yet, [[flagellin]], the main protein component of flagella, can act as an immunomodulator and activate the innate immune response in ''Hydra''. Therefore, bacteria have less chance to evade the immune system and to colonize host tissues.<ref name=":3" /> Another explanation is that 3-hydroxy-HSL induces carbon metabolism and fatty acid degradation genes in ''Hydra''. This allows the bacterial metabolism to adjust itself to the host growth conditions, which is essential for the colonization of the ectodermal mucus layer of ''Hydrae''.<ref name=":3" />

==== ''Enterococcus faecalis'' ====
''[[Enterococcus faecalis]]'' is an opportunistic, gram-positive bacteria that forms biofilm in glass. This process is also known as forming a biofilm in vitro. The presence of (Esp), a certain cell surface protein, aids the formation of a biofilm by ''E. faecalis''.<ref>{{cite journal | pmc=365672 | date=2004 | last1=Kristich | first1=C. J. | last2=Li | first2=Y. H. | last3=Cvitkovitch | first3=D. G. | last4=Dunny | first4=G. M. | title=Esp-Independent Biofilm Formation by Enterococcus faecalis | journal=Journal of Bacteriology | volume=186 | issue=1 | pages=154–163 | doi=10.1128/JB.186.1.154-163.2004 | pmid=14679235 }}</ref>

The ability of ''E. faecalis'' to form [[biofilm]]s contributes to its capacity to survive in extreme environments, and facilitates its involvement in persistent bacterial infection, particularly in the case of multi-drug resistant strains.<ref name = Schiopu2023>{{cite journal |vauthors=Șchiopu P, Toc DA, Colosi IA, Costache C, Ruospo G, Berar G, Gălbău ȘG, Ghilea AC, Botan A, Pană AG, Neculicioiu VS, Todea DA |title=An Overview of the Factors Involved in Biofilm Production by the Enterococcus Genus |journal=Int J Mol Sci |volume=24 |issue=14 |date=July 2023 |page=11577 |pmid=37511337 |pmc=10380289 |doi=10.3390/ijms241411577 |doi-access=free |url=}}</ref>  Biofilm formation in ''E. faecalis'' is associated with [[DNA]] release, and such release has emerged as a fundamental aspect of biofilm formation.<ref name = Schiopu2023/>  Conjugative [[plasmid]] DNA transfer in ''E. faecalis'' is enhanced by the release of peptide [[sex pheromone]]s.<ref>{{cite journal |vauthors=Hirt H, Greenwood-Quaintance KE, Karau MJ, Till LM, Kashyap PC, Patel R, Dunny GM |title=Enterococcus faecalis Sex Pheromone cCF10 Enhances Conjugative Plasmid Transfer In Vivo |journal=mBio |volume=9 |issue=1 |pages= |date=February 2018 |pmid=29440568 |pmc=5821081 |doi=10.1128/mBio.00037-18 |url=}}</ref>

==== ''Escherichia coli'' ====
In the gram-negative bacterium ''[[Escherichia coli]]'', cell division may be partially regulated by [[AI-2]]-mediated quorum sensing. This species uses AI-2, which is produced and processed by the ''[[Lipolysis-stimulated lipoprotein receptor|lsr]]'' [[operon]]. Part of it encodes an [[ABC transporter]], which imports AI-2 into the cells during the early stationary (latent) phase of growth. AI-2 is then phosphorylated by the LsrK [[kinase]], and the newly produced phospho-AI-2 can be either internalized or used to suppress LsrR, a repressor of the ''lsr'' operon (thereby activating the operon). Transcription of the ''lsr'' operon is also thought to be inhibited by [[dihydroxyacetone phosphate]] (DHAP) through its competitive binding to LsrR. [[Glyceraldehyde 3-phosphate]] has also been shown to inhibit the ''lsr'' operon through [[Cyclic adenosine monophosphate|cAMP]]-CAPK-mediated inhibition. This explains why, when grown with [[glucose]], ''E. coli'' will lose the ability to internalize AI-2 (because of [[catabolite repression]]). When grown normally, [[AI-2]] presence is transient.

''E. coli'' and ''Salmonella enterica'' do not produce AHL signals commonly found in other gram-negative bacteria. However, they have a receptor that detects AHLs from other bacteria and change their gene expression in accordance with the presence of other "quorate" populations of gram-negative bacteria.<ref>{{cite journal | vauthors = Ahmer BM | title = Cell-to-cell signalling in Escherichia coli and Salmonella enterica | journal = Molecular Microbiology | volume = 52 | issue = 4 | pages = 933–945 | date = May 2004 | pmid = 15130116 | doi = 10.1111/j.1365-2958.2004.04054.x | doi-access = free }}</ref> AHL quorum sensing regulates a wide range of genes through cell density. Other species of bacteria produce AHLs that ''Escherichia'' and ''Salmonella'' can detect. ''E. coli'' and ''Salmonella'' produce a receptor like protein (SdiA) allowing the amino acid sequence that is similar to AHL show AHLs can be found in the bovine rumen and ''E. coli'' responds to AHLs taken out of the bovine rumen. Most animals do not have AHL in their gastrointestinal tracts.<ref>{{cite journal | pmc=3078957 | date=2011 | last1=Soares | first1=J. A. | last2=Ahmer | first2=B. M. | title=Detection of acyl-homoserine lactones by Escherichia and Salmonella | journal=Current Opinion in Microbiology | volume=14 | issue=2 | pages=188–193 | doi=10.1016/j.mib.2011.01.006 | pmid=21353625 }}</ref>

====''Salmonella enterica''====
''[[Salmonella]]'' encodes a LuxR homolog, SdiA, but does not encode an AHL synthase. SdiA detects AHLs produced by other species of bacteria including ''[[Aeromonas hydrophila]]'', ''[[Hafnia alvei]]'', and ''[[Yersinia enterocolitica]]''.<ref>{{cite journal | vauthors = Michael B, Smith JN, Swift S, Heffron F, Ahmer BM | title = SdiA of Salmonella enterica is a LuxR homolog that detects mixed microbial communities | journal = Journal of Bacteriology | volume = 183 | issue = 19 | pages = 5733–5742 | date = October 2001 | pmid = 11544237 | pmc = 95466 | doi = 10.1128/JB.183.19.5733-5742.2001 }}</ref> When AHL is detected, SdiA regulates the ''rck'' operon on the ''Salmonella'' virulence plasmid (''pefI-srgD-srgA-srgB-rck-srgC'') and a single gene horizontal acquisition in the chromosome ''srgE''.<ref>{{cite journal | vauthors = Ahmer BM, van Reeuwijk J, Timmers CD, Valentine PJ, Heffron F | title = Salmonella typhimurium encodes an SdiA homolog, a putative quorum sensor of the LuxR family, that regulates genes on the virulence plasmid | journal = Journal of Bacteriology | volume = 180 | issue = 5 | pages = 1185–1193 | date = March 1998 | pmid = 9495757 | pmc = 107006 | doi = 10.1128/JB.180.5.1185-1193.1998 }}</ref><ref>{{cite journal | vauthors = Smith JN, Ahmer BM | title = Detection of other microbial species by Salmonella: expression of the SdiA regulon | journal = Journal of Bacteriology | volume = 185 | issue = 4 | pages = 1357–1366 | date = February 2003 | pmid = 12562806 | pmc = 142872 | doi = 10.1128/JB.185.4.1357-1366.2003 }}</ref> ''Salmonella'' does not detect AHL when passing through the gastrointestinal tracts of several animal species, suggesting that the normal microbiota does not produce AHLs. However, SdiA does become activated when ''Salmonella'' transits through turtles colonized with ''Aeromonas hydrophila'' or mice infected with ''Yersinia enterocolitica''.<ref>{{cite journal | vauthors = Smith JN, Dyszel JL, Soares JA, Ellermeier CD, Altier C, Lawhon SD, Adams LG, Konjufca V, Curtiss R, Slauch JM, Ahmer BM | display-authors = 6 | title = SdiA, an N-acylhomoserine lactone receptor, becomes active during the transit of Salmonella enterica through the gastrointestinal tract of turtles | journal = PLOS ONE | volume = 3 | issue = 7 | pages = e2826 | date = July 2008 | pmid = 18665275 | pmc = 2475663 | doi = 10.1371/journal.pone.0002826 | bibcode = 2008PLoSO...3.2826S | doi-access = free | editor = Ausubel, Frederick M. }}</ref><ref>{{cite journal | vauthors = Dyszel JL, Smith JN, Lucas DE, Soares JA, Swearingen MC, Vross MA, Young GM, Ahmer BM | display-authors = 6 | title = Salmonella enterica serovar Typhimurium can detect acyl homoserine lactone production by Yersinia enterocolitica in mice | journal = Journal of Bacteriology | volume = 192 | issue = 1 | pages = 29–37 | date = January 2010 | pmid = 19820103 | pmc = 2798265 | doi = 10.1128/JB.01139-09 }}</ref> Therefore, ''Salmonella'' appears to use SdiA to detect the AHL production of other pathogens rather than the normal gut flora.

====''Myxococcus xanthus''====
''[[Myxococcus]]'' is a genus of gram-negative bacterium in the Myxococcacae family. ''[[Myxococcus xanthus]]'' specifically, a bacillus myxobacteria species within [[Myxococcaceae|Myxococcae]], grows in the upper layers of soil. This bacterium is known for its unique utilization of quorum sensing practices to hunt.

The bacterium uniquely survives not on sugars, but [[lipid]]s created by the degradation of macromolecules lysed by the species. It hunts and feeds through a density-regulated method of predation that is "the regulation of gene expression in response to cell density."<ref name=":8">{{Cite journal| doi = 10.1111/j.1574-6976.2009.00185.x| issn = 0168-6445| volume = 33| issue = 5| pages = 942–957| last1 = Berleman| first1 = James E.| last2 = Kirby| first2 = John R.| title = Deciphering the hunting strategy of a bacterial wolfpack| journal = FEMS Microbiology Reviews| access-date = 2024-04-16| date = 2009-09-01| pmid = 19519767| pmc = 2774760| url = https://doi.org/10.1111/j.1574-6976.2009.00185.x}}</ref> The [[pilus]] propelled microorganism moves with the use of both S- and A- (or gliding) motility, which provide transportation across a dynamic range of different surfaces.<ref>{{Cite journal| issn = 0027-8424| volume = 90| issue = 8| pages = 3378–3382| last1 = Shi| first1 = W| last2 = Zusman| first2 = D R| title = The two motility systems of Myxococcus xanthus show different selective advantages on various surfaces.| journal = Proceedings of the National Academy of Sciences of the United States of America| date = 1993-04-15| doi = 10.1073/pnas.90.8.3378| doi-access = free| pmid = 8475084| pmc = 46303| bibcode = 1993PNAS...90.3378S}}</ref>  ''M. xanthus''{{'s}} A-motility is most effective in the presence of a single or low number of cells, allowing the bacteria to glide in high [[agar]] concentrations. The S-motility, or social motility, is controlled by the process of quorum sensing and is only effective when cells are within one cell length of a neighbor.<ref>{{Cite journal| doi = 10.1371/journal.pcbi.1005010| issn = 1553-7358| volume = 12| issue = 6| pages = –1005010| last1 = Patra| first1 = Pintu| last2 = Kissoon| first2 = Kimberley| last3 = Cornejo| first3 = Isabel| last4 = Kaplan| first4 = Heidi B.| last5 = Igoshin| first5 = Oleg A.| title = Colony Expansion of Socially Motile Myxococcus xanthus Cells Is Driven by Growth, Motility, and Exopolysaccharide Production| journal = PLOS Computational Biology| date = 2016-06-30| doi-access = free| pmid = 27362260| pmc = 4928896| bibcode = 2016PLSCB..12E5010P}}</ref>  Although the precise specifics of ''M. xanthus''{{'s}} communication methods for quorum sensing are not well understood, the bacteria mediate the process by using both C-signal and A-factor. The A-factor molecule, produced by ''M. xanthus'', must reach a set concentration to initiate aggregation for hunting.<ref>{{Cite journal| doi = 10.3389/fmicb.2017.00439| issn = 1664-302X| volume = 8| pages = 439| last1 = Lloyd| first1 = Daniel G.| last2 = Whitworth| first2 = David E.| title = The Myxobacterium Myxococcus xanthus Can Sense and Respond to the Quorum Signals Secreted by Potential Prey Organisms| journal = Frontiers in Microbiology| date = 2017-03-14| doi-access = free| pmid = 28352265| pmc = 5348527}}</ref>  The C-signal concentration, on the other hand, plays a role in [[Fruiting body (bacteria)|fruiting body]] production.

The species is known for its ability to use quorum sensing to hunt in special packs with thousands of individual cells, lending to ''M. xanthus''{{'s}} name "the wolf packs." ''M. xanthus'' is inclined to behave in a [[Multicellular organism|multicellular]] fashion. In the presence of many cells, it uses these "wolf packs" to form "highly structured [[biofilm]]s that include tentacle-like packs of surface-gliding cell groups, synchronized rippling waves of oscillating cells and massive spore-filled aggregates that protrude upwards from the substratum to form fruiting bodies."<ref>{{Cite journal| doi = 10.3389/fmicb.2022.894562| issn = 1664-302X| volume = 13| pages = 894562| last1 = Dye| first1 = Keane J.| last2 = Yang| first2 = Zhaomin| title = Analysis of Myxococcus xanthus Vegetative Biofilms With Microtiter Plates| journal = Frontiers in Microbiology| date = 2022-04-29| doi-access = free| pmid = 35572678| pmc = 9100584}}</ref><ref name=":8" /> On the fringes of this film, individual cells can be observed "gliding across the surface, but the majority of cells are observed in large tendril-shaped groups" using S-motility.<ref name=":8" />

==== ''Staphylococcus aureus'' ====
''Staphylococcus aureus'' is a type of pathogen that causes infection to the skin and soft tissue and can lead to a variety of more severe diseases such as osteomyelitis, pneumonia, and endocarditis. ''S. aureus'' uses biofilms in order to increase its chances of survival by becoming resistant to antibiotics. Biofilms help ''S. aureus'' become up to 1500 times more resistant to antibiofilm agents, which try to break down biofilms formed by ''S. aureus''.<ref>{{cite journal |last1=Wu |first1=Xiying |last2=Wang |first2=Huan |last3=Xiong |first3=Juan |last4=Yang |first4=Guo-Xun |last5=Hu |first5=Jin-Feng |last6=Zhu |first6=Quangang |last7=Chen |first7=Zhongjian |title=Staphylococcus aureus biofilm: Formulation, regulatory, and emerging natural products-derived therapeutics |journal=Biofilm |date=June 2024 |volume=7 |pages=100175 |doi=10.1016/j.bioflm.2023.100175 |pmid=38298832 |pmc=10827693 }}</ref>

====''Streptococcus pneumoniae''====

Each year ''Streptococcus pneumoniae'' kills more than a million people, even though vaccines are available.<ref>{{cite journal |vauthors=Junges R, Salvadori G, Shekhar S, Åmdal HA, Periselneris JN, Chen T, Brown JS, Petersen FC |title=A Quorum-Sensing System That Regulates Streptococcus pneumoniae Biofilm Formation and Surface Polysaccharide Production |journal=mSphere |volume=2 |issue=5 |pages= |date=2017 |pmid=28932816 |pmc=5597970 |doi=10.1128/mSphere.00324-17 |url=}}</ref>  A complex quorum sensing system has evolved in ''S. pneumoniae'' that regulates [[bacteriocin]] production.  This system also enables entry into the [[natural competence|competent state]] essential for natural [[genetic transformation]].<ref>{{cite journal |vauthors=Shanker E, Federle MJ |title=Quorum Sensing Regulation of Competence and Bacteriocins in Streptococcus pneumoniae and mutans |journal=Genes (Basel) |volume=8 |issue=1 |date=January 2017 |page=15 |pmid=28067778 |doi=10.3390/genes8010015 |doi-access=free |pmc=5295010 |url=}}</ref>  In naturally competent ''S. pneumoniae'' the competent state is not a constitutive property.  However competence can be induced by a peptide [[pheromone]] by means of  a quorum-sensing mechanism.<ref name = Steinmoen2002>{{cite journal |vauthors=Steinmoen H, Knutsen E, Håvarstein LS |title=Induction of natural competence in Streptococcus pneumoniae triggers lysis and DNA release from a subfraction of the cell population |journal=Proc Natl Acad Sci U S A |volume=99 |issue=11 |pages=7681–6 |date=May 2002 |pmid=12032343 |doi=10.1073/pnas.112464599 |doi-access=free |pmc=124321 |bibcode=2002PNAS...99.7681S |url=}}</ref>  When the competent state is induced, this causes release of [[DNA]] from a sub-fraction of the ''S. pneumoniae'' population, probably by cell lysis.  Then most of the ''S. pneumoniae'' cells that have been induced to competence become recipients and take up the DNA released by the donors.<ref name = Steinmoen2002/>  Thus it appears that natural transformation in ''S. pneumoniae'' is a natural adaptive process for promoting [[genetic recombination]], a process that resembles [[sexual reproduction]] in higher organisms.<ref name = Steinmoen2002/>

====''Pseudomonas aeruginosa''====
The environmental bacterium and opportunistic pathogen ''[[Pseudomonas aeruginosa]]'' uses quorum sensing to coordinate the formation of [[biofilm]], [[swarming motility]], [[exopolysaccharide]] production, virulence, and cell aggregation.<ref>{{cite journal | vauthors = Sauer K, Camper AK, Ehrlich GD, Costerton JW, Davies DG | title = Pseudomonas aeruginosa displays multiple phenotypes during development as a biofilm | journal = Journal of Bacteriology | volume = 184 | issue = 4 | pages = 1140–1154 | date = February 2002 | pmid = 11807075 | pmc = 134825 | doi = 10.1128/jb.184.4.1140-1154.2002 }}</ref> These bacteria can grow within a host without harming it until they reach a threshold concentration. Then they become aggressive, developing to the point at which their numbers are sufficient to overcome the host's [[immune system]], and form a [[biofilm]], leading to [[disease]] within the host as the biofilm is a protective layer encasing the bacterial population.{{citation needed|date=July 2022}} The relative ease of growth, handling, and genetic manipulation of ''P. aeruginosa'' has lent much research effort to the quorum sensing circuits of this relatively common bacterium. Quorum sensing in ''P. aeruginosa'' typically encompasses two complete AHL synthase-receptor circuits, LasI-LasR and RhlI-RhlR, as well as the orphan receptor-regulator QscR, which is also activated by the LasI-generated signal.<ref>{{cite journal |last1=Schuster |first1=Martin |last2=Peter Greenberg |first2=E. |title=A network of networks: Quorum-sensing gene regulation in Pseudomonas aeruginosa |journal=International Journal of Medical Microbiology |date=April 2006 |volume=296 |issue=2–3 |pages=73–81 |doi=10.1016/j.ijmm.2006.01.036 |pmid=16476569 }}</ref> Together, the multiple AHL quorum sensing circuits of ''P. aeruginosa'' influence regulation of hundreds of genes.

Another form of [[gene regulation]] that allows the [[bacteria]] to rapidly adapt to surrounding changes is through environmental signaling. Recent studies have discovered that [[anaerobiosis]] can significantly impact the major regulatory circuit of quorum sensing. This important link between quorum sensing and anaerobiosis has a significant impact on the production of virulence factors of this [[organism]].<ref name="Cornelis">{{cite book |editor=Cornelis, P. |title=Pseudomonas: Genomics and Molecular Biology |url= http://www.horizonpress.com/pseudo |edition=1st |year=2008 |publisher=Caister Academic Press |isbn=978-1-904455-19-6 |access-date=1 May 2022}}</ref> There is hope among some humans that the therapeutic enzymatic degradation of the signaling molecules will be possible when treating illness caused by biofilms, and prevent the formation of such biofilms and possibly weaken established biofilms. Disrupting the signaling process in this way is called ''quorum sensing inhibition''.<ref>{{cite journal |last1=Ma |first1=Yeping |last2=Tang |first2=Wing Suet |last3=Liu |first3=Sylvia Yang |last4=Khoo |first4=Bee Luan |last5=Chua |first5=Song Lin |title=Juglone as a Natural Quorum Sensing Inhibitor against Pseudomonas aeruginosa pqs-Mediated Virulence and Biofilms |journal=ACS Pharmacology & Translational Science |date=9 February 2024 |volume=7 |issue=2 |pages=533–543 |doi=10.1021/acsptsci.3c00354 |pmid=38357290 |pmc=10863437 }}</ref>

====''Acinetobacter'' sp.====
It has recently been found that ''[[Acinetobacter]]'' sp. also show quorum sensing activity. This bacterium, an emerging pathogen, produces AHLs.<ref name="biomedcentral">{{cite journal | vauthors = Chan KG, Atkinson S, Mathee K, Sam CK, Chhabra SR, Cámara M, Koh CL, Williams P | display-authors = 6 | title = Characterization of N-acylhomoserine lactone-degrading bacteria associated with the Zingiber officinale (ginger) rhizosphere: co-existence of quorum quenching and quorum sensing in Acinetobacter and Burkholderia | journal = BMC Microbiology | volume = 11 | issue = 1 <!-- |access-date=1 May 2022 --> | pages = 51 | date = March 2011 | pmid = 21385437 | pmc = 3062576 | doi = 10.1186/1471-2180-11-51 | doi-access = free }}</ref> ''Acinetobacter'' sp. shows both quorum sensing and quorum quenching activity. It produces AHLs and can also degrade the AHL molecules.<ref name="biomedcentral"/>

====''Aeromonas'' sp.====
This bacterium was previously considered a fish pathogen, but it has recently emerged as a human pathogen.<ref>{{cite journal | vauthors = Igbinosa IH, Igumbor EU, Aghdasi F, Tom M, Okoh AI | title = Emerging Aeromonas species infections and their significance in public health | journal = TheScientificWorldJournal | volume = 2012 | pages = 625023 | year = 2012 | pmid = 22701365 | pmc = 3373137 | doi = 10.1100/2012/625023 | doi-access = free }}</ref> ''[[Aeromonas]]'' sp. have been isolated from various infected sites from patients (bile, blood, peritoneal fluid, pus, stool and urine). All isolates produced the two principal AHLs, N-butanoylhomoserine lactone (C4-HSL) and N-hexanoyl homoserine lactone (C6-HSL). It has been documented that ''Aeromonas sobria'' has produced C6-HSL and two additional AHLs with N-acyl side chain longer than C6.<ref name="Current Microbiology">{{cite journal | vauthors = Chan KG, Puthucheary SD, Chan XY, Yin WF, Wong CS, Too WS, Chua KH | title = Quorum sensing in Aeromonas species isolated from patients in Malaysia | journal = Current Microbiology | volume = 62 | issue = 1 | pages = 167–172 | date = January 2011 | pmid = 20544198 | doi = 10.1007/s00284-010-9689-z | s2cid = 6761810 <!-- |access-date=1 May 2022 --> }}</ref>

====''Yersinia ''====
The YenR and YenI proteins produced by the [[gammaproteobacterium]] ''[[Yersinia enterocolitica]]'' are similar to ''Aliivibrio fischeri'' LuxR and LuxI.<ref>{{cite journal | vauthors = Throup JP, Camara M, Briggs GS, Winson MK, Chhabra SR, Bycroft BW, Williams P, Stewart GS | display-authors = 6 | title = Characterisation of the yenI/yenR locus from Yersinia enterocolitica mediating the synthesis of two N-acylhomoserine lactone signal molecules | journal = Molecular Microbiology | volume = 17 | issue = 2 | pages = 345–356 | date = July 1995 | pmid = 7494483 | doi = 10.1111/j.1365-2958.1995.mmi_17020345.x | s2cid = 3100775 }}</ref><ref name="Atkinson 1451–61">{{cite journal | vauthors = Atkinson S, Chang CY, Sockett RE, Cámara M, Williams P | title = Quorum sensing in Yersinia enterocolitica controls swimming and swarming motility | journal = Journal of Bacteriology | volume = 188 | issue = 4 | pages = 1451–1461 | date = February 2006 | pmid = 16452428 | pmc = 1367215 | doi = 10.1128/JB.188.4.1451-1461.2006 }}</ref> YenR activates the expression of a [[Bacterial small RNA|small non-coding RNA]], YenS. YenS inhibits YenI expression and acylhomoserine lactone production.<ref name="Tsai 556–71">{{cite journal | vauthors = Tsai CS, Winans SC | title = The quorum-hindered transcription factor YenR of Yersinia enterocolitica inhibits pheromone production and promotes motility via a small non-coding RNA | journal = Molecular Microbiology | volume = 80 | issue = 2 | pages = 556–571 | date = April 2011 | pmid = 21362062 | doi = 10.1111/j.1365-2958.2011.07595.x | doi-access = free }}</ref> YenR/YenI/YenS are involved in the control of swimming and swarming motility.<ref name="Atkinson 1451–61"/><ref name="Tsai 556–71"/>

====''[[Vibrio cholerae]]''====

''V. cholerae'' is a bacterial pathogen that causes [[cholera]], a disease associated with severe contagious diarrhea that affects millions of people worldwide.  ''V. cholerae'' is capable of strong communication between cells, and this process is referred to as quorum-sensing.<ref>{{cite journal |vauthors=Sajeevan A, Ramamurthy T, Solomon AP |title=Vibrio cholerae virulence and its suppression through the quorum-sensing system |journal=Crit Rev Microbiol |volume= 51|issue= 1|pages=22–43 |date=March 2024 |pmid=38441045 |doi=10.1080/1040841X.2024.2320823 |url=}}</ref><ref>{{cite journal |vauthors=Li Y, Yan J, Li J, Xue X, Wang Y, Cao B |title=A novel quorum sensing regulator LuxT contributes to the virulence of Vibrio cholerae |journal=Virulence |volume=14 |issue=1 |pages=2274640 |date=December 2023 |pmid=37908129 |pmc=10621291 |doi=10.1080/21505594.2023.2274640 |url=}}</ref>  In the small intestine, the absence of oxygen and exposure to host-produced [[bile acid|bile salts]], influence ''V. cholerae'' quorum sensing function and thus its pathogenicity.<ref>{{cite journal |vauthors=Mashruwala AA, Bassler BL |title=The Vibrio cholerae Quorum-Sensing Protein VqmA Integrates Cell Density, Environmental, and Host-Derived Cues into the Control of Virulence |journal=mBio |volume=11 |issue=4 |pages= |date=July 2020 |pmid=32723922 |pmc=7387800 |doi=10.1128/mBio.01572-20 |url=}}</ref>  Quorum sensing appears to contribute to natural [[genetic transformation]], a process that involves the uptake of ''V. cholerae'' extracellular DNA by ([[natural competence|competent]]) ''V. cholerae'' cells.<ref>{{cite journal |vauthors=Blokesch M |title=A quorum sensing-mediated switch contributes to natural transformation of Vibrio cholerae |journal=Mob Genet Elements |volume=2 |issue=5 |pages=224–227 |date=September 2012 |pmid=23446800 |doi=10.4161/mge.22284 |pmc=3575429 |url=}}</ref>

===Molecules involved===
Three-dimensional structures of proteins involved in quorum sensing were first published in 2001, when the [[crystal structure]]s of three [[LuxS]] [[Homology (biology)#Orthology|orthologs]] were determined by [[X-ray crystallography]].<ref>{{cite journal | vauthors = Lewis HA, Furlong EB, Laubert B, Eroshkina GA, Batiyenko Y, Adams JM, Bergseid MG, Marsh CD, Peat TS, Sanderson WE, Sauder JM, Buchanan SG | display-authors = 6 | title = A structural genomics approach to the study of quorum sensing: crystal structures of three LuxS orthologs | journal = Structure | volume = 9 | issue = 6 | pages = 527–537 | date = June 2001 | pmid = 11435117 | doi = 10.1016/S0969-2126(01)00613-X | doi-access = free }}</ref> In 2002, the crystal structure of the receptor LuxP of ''[[Vibrio harveyi]]'' with its inducer [[AI-2]] (which is one of the few [[biomolecules]] containing [[boron]]) bound to it was also determined.<ref>{{cite journal | vauthors = Chen X, Schauder S, Potier N, Van Dorsselaer A, Pelczer I, Bassler BL, Hughson FM | title = Structural identification of a bacterial quorum-sensing signal containing boron | journal = Nature | volume = 415 | issue = 6871 | pages = 545–549 | date = January 2002 | pmid = 11823863 | doi = 10.1038/415545a }}</ref> Many bacterial species, including ''[[E. coli]]'', an enteric bacterium and model organism for gram-negative bacteria, produce AI-2. A comparative genomic and phylogenetic analysis of 138 genomes of bacteria, [[archaea]], and eukaryotes found that "the LuxS enzyme required for AI-2 synthesis is widespread in bacteria, while the [[periplasmic space|periplasmic]] [[binding protein]] LuxP is present only in ''Vibrio'' strains," leading to the conclusion that either "other organisms may use components different from the AI-2 signal transduction system of ''Vibrio'' strains to sense the signal of AI-2 or they do not have such a quorum sensing system at all."<ref name="pmid15456522">{{cite journal | vauthors = Sun J, Daniel R, Wagner-Döbler I, Zeng AP | title = Is autoinducer-2 a universal signal for interspecies communication: a comparative genomic and phylogenetic analysis of the synthesis and signal transduction pathways | journal = BMC Evolutionary Biology | volume = 4 | issue = 1 | pages = 36 | date = September 2004 | pmid = 15456522 | pmc = 524169 | doi = 10.1186/1471-2148-4-36 | doi-access = free }}</ref> ''Vibrio'' species utilize [[Qrr RNA]]s, small non-coding RNAs, that are activated by these autoinducers to target cell density master regulators. [[Farnesol]] is used by the fungus ''[[Candida albicans]]'' as a quorum sensing molecule that inhibits [[filamentation]].<ref>{{cite journal | vauthors = Hornby JM, Jensen EC, Lisec AD, Tasto JJ, Jahnke B, Shoemaker R, Dussault P, Nickerson KW | display-authors = 6 | title = Quorum sensing in the dimorphic fungus Candida albicans is mediated by farnesol | journal = Applied and Environmental Microbiology | volume = 67 | issue = 7 | pages = 2982–2992 | date = July 2001 | pmid = 11425711 | pmc = 92970 | doi = 10.1128/AEM.67.7.2982-2992.2001 | bibcode = 2001ApEnM..67.2982H }}</ref>

A database of quorum-sensing peptides is available under the name Quorumpeps.<ref>{{cite journal | vauthors = Wynendaele E, Bronselaer A, Nielandt J, D'Hondt M, Stalmans S, Bracke N, Verbeke F, Van De Wiele C, De Tré G, De Spiegeleer B | display-authors = 6 | title = Quorumpeps database: chemical space, microbial origin and functionality of quorum sensing peptides | journal = Nucleic Acids Research | volume = 41 | issue = Database issue | pages = D655–D659 | date = January 2013 | pmid = 23180797 | pmc = 3531179 | doi = 10.1093/nar/gks1137 }}</ref><ref>{{cite journal | vauthors = Wynendaele E, Gevaert B, Stalmans S, Verbeke F, De Spiegeleer B | title = Exploring the chemical space of quorum sensing peptides | journal = Biopolymers | volume = 104 | issue = 5 | pages = 544–551 | date = September 2015 | pmid = 25846138 | doi = 10.1002/bip.22649 | s2cid = 21031922 }}</ref>

Certain bacteria can produce enzymes called [[lactonase]]s that can target and inactivate AHLs.
Researchers have developed novel molecules which block the signalling receptors of bacteria ("Quorum quenching"). mBTL is a compound that has been shown to inhibit quorum sensing and decrease the amount of cell death by a significant amount.<ref>{{cite journal | vauthors = O'Loughlin CT, Miller LC, Siryaporn A, Drescher K, Semmelhack MF, Bassler BL | title = A quorum-sensing inhibitor blocks Pseudomonas aeruginosa virulence and biofilm formation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 44 | pages = 17981–17986 | date = October 2013 | pmid = 24143808 | pmc = 3816427 | doi = 10.1073/pnas.1316981110 | bibcode = 2013PNAS..11017981O | doi-access = free }}</ref>
Additionally, researchers are also examining the role of natural compounds (such as [[caffeine]]) as potential quorum sensing inhibitors.<ref>{{cite journal | vauthors = Norizan SN, Yin WF, Chan KG | title = Caffeine as a potential quorum sensing inhibitor | journal = Sensors | volume = 13 | issue = 4 | pages = 5117–5129 | date = April 2013 | pmid = 23598500 | pmc = 3673129 | doi = 10.3390/s130405117 | bibcode = 2013Senso..13.5117N | doi-access = free }}</ref> Research in this area has been promising and could lead to the development of natural compounds as effective therapeutics.

===Evolution===

====Sequence analysis====
The majority of quorum sensing systems that fall under the "two-gene" (an autoinducer synthase coupled with a receptor molecule) paradigm as defined by the ''[[Vibrio fischeri]]'' system occur in the [[gram-negative]] [[Pseudomonadota]]. A comparison between the Pseudomonadota [[phylogeny]] as generated by [[16S ribosomal RNA]] sequences and phylogenies of LuxI-, LuxR-, or LuxS-homologs shows a notably high level of global similarity. Overall, the quorum sensing genes seem to have diverged along with the Pseudomonadota phylum as a whole. This indicates that these quorum sensing systems are quite ancient, and arose very early in the Pseudomonadota lineage.<ref name="gray-2001">{{cite journal | vauthors = Gray KM, Garey JR | title = The evolution of bacterial LuxI and LuxR quorum sensing regulators | journal = Microbiology | volume = 147 | issue = Pt 8 | pages = 2379–2387 | date = August 2001 | pmid = 11496014 | doi = 10.1099/00221287-147-8-2379 | doi-access = free }}</ref><ref name="lerat-2004">{{cite journal | vauthors = Lerat E, Moran NA | title = The evolutionary history of quorum-sensing systems in bacteria | journal = Molecular Biology and Evolution | volume = 21 | issue = 5 | pages = 903–913 | date = May 2004 | pmid = 15014168 | doi = 10.1093/molbev/msh097 | doi-access = free }}</ref>

LuxI and LuxR have coevolved through a long history of horizontal gene transfer (HGT) events. An early study reconciling their gene trees with the rRNA tree suggested frequent HGT events for both LuxI and LuxR, indicating that they are horizontally transferred together and coevolve due to their functional dependency.<ref name="gray-2001" /> Similarly, in QS systems in bacteria associated with ''Populus deltoides'', the gene trees for ''luxI'' and ''luxR'' show high topological similarity, indicating coevolution of cognate pairs.<ref name=":9">{{Cite journal |last1=Schaefer |first1=Amy L. |last2=Lappala |first2=Colin R. |last3=Morlen |first3=Ryan P. |last4=Pelletier |first4=Dale A. |last5=Lu |first5=Tse-Yuan S. |last6=Lankford |first6=Patricia K. |last7=Harwood |first7=Caroline S. |last8=Greenberg |first8=E. Peter |date=2013-09-15 |title=LuxR- and LuxI-Type Quorum-Sensing Circuits Are Prevalent in Members of the Populus deltoides Microbiome |journal=Applied and Environmental Microbiology |language=en |volume=79 |issue=18 |pages=5745–5752 |doi=10.1128/AEM.01417-13 |issn=0099-2240 |pmc=3754149 |pmid=23851092|bibcode=2013ApEnM..79.5745S }}</ref> In addition to horizontal transfer of complete LuxI/LuxR-type QS systems, many Proteobacteria genomes exhibit an excess of LuxR genes or cases with only LuxR but not LuxI, acquired from different sources via HGT.<ref name=":9" /> Due to the frequent transfer of functional pairs of homologs (i.e., LuxI/LuxR-type systems from multiple independent sources), it is possible that the regulatory hierarchy formed by the LuxI/LuxR and RhlR-RhlI systems is a result of sequential integration of circuits obtained from different sources, due to interactions between multiple homologs.<ref name="gray-2001" /> Interestingly, LuxI genes have likely undergone horizontal gene transfer from Proteobacteria to other lineages, as they have been detected in Nitrospira lineage II.<ref>{{Cite journal |last1=Mellbye |first1=Brett L. |last2=Spieck |first2=Eva |last3=Bottomley |first3=Peter J. |last4=Sayavedra-Soto |first4=Luis A. |date=2017-11-15 |editor-last=Parales |editor-first=Rebecca E. |title=Acyl-Homoserine Lactone Production in Nitrifying Bacteria of the Genera Nitrosospira, Nitrobacter, and Nitrospira Identified via a Survey of Putative Quorum-Sensing Genes |journal=Applied and Environmental Microbiology |language=en |volume=83 |issue=22 |doi=10.1128/AEM.01540-17 |issn=0099-2240 |pmc=5666142 |pmid=28887424|bibcode=2017ApEnM..83E1540M }}</ref>

In quorum sensing genes of [[Gammaproteobacteria]], which includes ''[[Pseudomonas aeruginosa]]'' and ''[[Escherichia coli]]'', the LuxI/LuxR genes form a functional pair, with LuxI as the auto-inducer synthase and LuxR as the receptor. Gammaproteobacteria are unique in possessing quorum sensing genes, which, although functionally similar to the LuxI/LuxR genes, have a markedly divergent sequence.<ref name="lerat-2004"/> This family of quorum-sensing [[homology (biology)|homologs]] may have arisen in the Gammaproteobacteria ancestor, although the cause of their extreme sequence divergence yet maintenance of functional similarity has yet to be explained. In addition, species that employ multiple discrete quorum sensing systems are almost all members of the Gammaproteobacteria, and evidence of horizontal transfer of quorum sensing genes is most evident in this class.<ref name="gray-2001"/><ref name="lerat-2004"/>

====Interaction of quorum-sensing molecules with mammalian cells and its medical applications====
Next to the potential antimicrobial functionality, quorum-sensing derived molecules, especially the peptides, are being investigated for their use in other therapeutic domains as well, including immunology, central nervous system disorders and oncology. Quorum-sensing peptides have been demonstrated to interact with cancer cells, as well as to permeate the blood–brain barrier reaching the brain parenchyma.<ref>{{cite journal | vauthors = De Spiegeleer B, Verbeke F, D'Hondt M, Hendrix A, Van De Wiele C, Burvenich C, Peremans K, De Wever O, Bracke M, Wynendaele E | display-authors = 6 | title = The quorum sensing peptides PhrG, CSP and EDF promote angiogenesis and invasion of breast cancer cells in vitro | journal = PLOS ONE | volume = 10 | issue = 3 | pages = e0119471 | year = 2015 | pmid = 25780927 | pmc = 4363635 | doi = 10.1371/journal.pone.0119471 | bibcode = 2015PLoSO..1019471D | doi-access = free }}</ref><ref>{{cite journal | vauthors = Wynendaele E, Verbeke F, D'Hondt M, Hendrix A, Van De Wiele C, Burvenich C, Peremans K, De Wever O, Bracke M, De Spiegeleer B | display-authors = 6 | title = Crosstalk between the microbiome and cancer cells by quorum sensing peptides | journal = Peptides | volume = 64 | pages = 40–48 | date = February 2015 | pmid = 25559405 | doi = 10.1016/j.peptides.2014.12.009 | hdl-access = free | s2cid = 28064836 | hdl = 2263/59248 }}</ref><ref>{{cite journal | vauthors = Wynendaele E, Verbeke F, Stalmans S, Gevaert B, Janssens Y, Van De Wiele C, Peremans K, Burvenich C, De Spiegeleer B | display-authors = 6 | title = Quorum Sensing Peptides Selectively Penetrate the Blood-Brain Barrier | journal = PLOS ONE | volume = 10 | issue = 11 | pages = e0142071 | date = Nov 2015 | pmid = 26536593 | pmc = 4633044 | doi = 10.1371/journal.pone.0142071 | bibcode = 2015PLoSO..1042071W | doi-access = free }}</ref>

=== Role of quorum sensing in biofilm development ===
Quorum sensing (QS) is used by bacteria to form biofilms. Quorum sensing is used by bacteria to form biofilms because the process determines if the minimum number of bacteria necessary for biofilm formation are present. The criteria to form a biofilm is dependent on a certain density of bacteria rather than a certain number of bacteria being present. When aggregated in high enough densities, some bacteria may form biofilms to protect themselves from biotic or abiotic threats.<ref name=":5">{{Cite journal |last1=Bogino |first1=P |last2=de las Mercedes Oliva |first2=M |date=July 30, 2013 |title=The Role of Bacterial Biofilms and Surface Components in Plant-Bacterial Associations |journal=International Journal of Molecular Sciences |volume=14 |issue=8 |pages=15838–15859 |doi=10.3390/ijms140815838 |pmid=23903045 |pmc=3759889 |doi-access=free}}</ref> Quorum sensing is used by both Gram-positive and Gram-negative bacteria because it aids cellular reproduction. Once in a biofilm, bacteria can communicate with other bacteria of the same species. Bacteria can also communicate with other species of bacteria. This communication is enabled through autoinducers used by the bacteria.<ref name="Miller Bassler 2001">{{cite journal |last1=Miller |first1=Melissa B. |last2=Bassler |first2=Bonnie L. |title=Quorum Sensing in Bacteria |journal=Annual Review of Microbiology |date=October 2001 |volume=55 |issue=1 |pages=165–199 |doi=10.1146/annurev.micro.55.1.165 |pmid=11544353 }}</ref>

Additionally, certain responses can be generated by the host organism in response to the certain bacterial autoinducers. Despite the fact that specific bacterial quorum sensing systems are different, for example the target genes, signal relay mechanisms, and chemical signals used between bacteria, the ability to coordinate gene expression for a specific species of bacteria remains the same. This ability alludes to the larger idea that bacteria have potential to become a multicellular bacterial body.<ref name="Miller Bassler 2001"/>

Secondly, biofilms may also serve to transport nutrients into the microbial community or transport toxins out by means of channels that permeate the extracellular polymeric matrix (like cellulose) that holds the cells together. Finally, biofilms are an ideal environment for horizontal gene transfer through either conjugation or environmental DNA (eDNA) that exists in the biofilm matrix.<ref name=":5"/>

The process of biofilm development is often triggered by environmental signals, and bacteria are proven to require flagella to successfully approach a surface, adhere to it, and form the biofilm.<ref name=":5" /> As cells either replicate or aggregate in a location, the concentration of autoinducers outside of the cells increases until a critical mass threshold is reached. At this point, it is energetically unfavorable for intracellular autoinducers to leave the cell and they bind to receptors and trigger a signaling cascade to initiate gene expression and begin secreting an extracellular polysaccharide to encase themselves inside.<ref>{{cite news |last1=Windsor |first1=W. Jon |title=How Quorum Sensing Works |url=https://asm.org/Articles/2020/June/How-Quorum-Sensing-Works |work=American Society for Microbiology |date=12 June 2020 }}</ref>

One modern method of preventing biofilm development without the use of antibiotics is with anti-QS substances, such ([[naringenin]], [[taxifolin]], etc.) that can be utilized as alternative form of therapy against bacterial virulence.<ref>{{Cite journal |last1=Jiang |first1=Qian |last2=Chen |first2=Jiashun |last3=Yang |first3=Chengbo |last4=Yin |first4=Yulong |last5=Yao |first5=Kang |date=2019-04-04 |title=Quorum Sensing: A Prospective Therapeutic Target for Bacterial Diseases |journal=BioMed Research International |language=en |volume=2019 |pages=e2015978 |doi=10.1155/2019/2015978 |doi-access=free |pmid=31080810 |pmc=6475571 |issn=2314-6133}}</ref>