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Sunday, December 2, 2007

Quorum Sensing

Researched by Alex

Quorum sensing is the process by which many bacteria coordinate gene expression according to the local density of bacteria producing signaling molecules.


The consequence of quorum sensing is the coordination of certain behavior or actions between bacteria, based on the local density of bacteria. Quorum sensing can occur within a single bacterial species as well as between disparate species, and can regulate a host of different processes, essentially serving as a simple communication network.

For example, opportunistic bacteria, such as Pseudomonas aeruginosa can grow within a host without harming it, until they reach a certain concentration. Then they become aggressive, their numbers sufficient to overcome the host's immune system and form a biofilm, leading to disease. It is hoped that the therapeutic enzymatic degradation of the signalling molecules will prevent the formation of such biofilms and possibly weaken established biofilms. Disrupting the signalling process in this way is called quorum quenching.


The relevant mathematics for the behavior and coordination of the bacteria is found in the allometric scaling equation known as Kleiber's Law, relating metabolic rate to organism mass and metabolic efficiency [P = W(4μ-1)/4μ] where P is metabolic rate, W is organism mass, and μ is metabolic efficiency - the ratio of rate of reduction reactions to rate of flow of energy from oxidation reactions. When the numbers are run for this equation for values of μ from 0 to 100%, and for values of W from e-13 grams to e+13 grams, what is revealed is that extremely small organisms, the size of bacteria, have very high metabolic rates which drop off rapidly with increases in mass. The equation implies then that cellular division of bacteria is a response to this diminution, an attempt to increase metabolic rate of the individual bacterium through its loss of mass by division. Notice that quorum sensing is dependent upon the number or mass density of bacteria. The equation is relevant on this score.

Unless the proliferating bacteria are diffused by circumstance, they remain in close proximity to each other. As the bacterial mass increases what is seen is a colony of bacteria, a new organism of sorts, still very, very small. The metabolic rate of the colony includes, but is not limited to, the basal metabolic rates of all its constituent bacteria, and is subject to the same loss of metabolic rate that comes with mass increase for the individual bacterium. These colonies can at times grow to considerable size, and are responsible for stromatolites, the oldest fossils on earth found in the coastal waters off Australia.

But mathematics also shows that with increases in mass, loss of metabolic rate is not so severe if μ or metabolic efficiency also increases. The math shows that increases in mass result in loss of metabolic rate for all organisms with a μ of less than 25%, and that as they approach this value for μ, the loss of metabolic rate becomes less with further increases in mass. Furthermore, the math shows that for things as small as single-celled organisms [e-5 grams], at μ greater than 25%, metabolic rate rapidly approaches zero unless mass is increased, not decreased. Consideration of the term μ reveals that to increase the value for μ either available energy must be reduced [the denominator, rate of flow of energy from oxidative sources], or the rate of reduction reactions [the numerator] must be increased.

Diminishing the denominator through the restriction of energy is something that usually takes place from circumstance, energy not being free. Increasing the numerator is done by the bacteria through energy expenditure appearing as the chemical production of organic substances like biofilms, or the generation of luminescence. In other words, at very small mass, biological organisms like bacteria and bacterial colonies, preserve their metabolic rates and perpetuate their existence and growth, through either division, the production of organic molecules, or the generation of light; and that at over 25% μ, to keep metabolic rate from crashing, very small things must increase in mass, something that follows from increased energy expenditure [the numerator of μ] in the creation of organic molecules.

What the math makes clear is that the purpose of quorum sensing is not a conscious attempt on the part of bacteria to coordinate behavior. The purpose of quorum sensing seems to be a chemical response of very small biological organisms to recoup loss of metabolic rate that follows from increases in mass at a value for μ below 25%. Attempts to understand the purpose of quorum sensing solely in terms of the chemical details of the mechanics of receptors and inducers, cloud understanding of the purpose of quorum sensing, and rest ultimately on a bit of quasi-anthropomorphism.

Methods and mechanisms

Bacteria that use quorum sensing produce and secrete certain signaling compounds (called autoinducers or pheromones), one example of which are N-acyl homoserine lactones (AHL). These bacteria also have a receptor that can specifically detect the AHL (inducer). When the inducer binds the receptor, it activates transcription of certain genes, including those for inducer synthesis. There is a low likelihood of a bacterium detecting its own secreted AHL.

When only a few other bacteria of the same kind are in the vicinity, diffusion reduces the concentration of the inducer in the surrounding medium to almost zero, so the bacteria produce little inducer. With many bacteria of the same kind, the concentration of the inducer passes a threshold, whereupon more inducer is synthesized. This forms a positive feedback loop, and the receptor becomes fully activated. This induces the up regulation of other specific genes, such as luciferase in V. fischeri. This is useful since a single V. fischeri bacterium that is luminescent would have no evolutionary advantage and would be wasting energy.

In Escherichia coli, AI-2 is produced by the lsr operon, encoding an ABC transporter which imports AI-2 into the cells during the early stationary (latent) phase of growth. AI-2 is then phosphorylated by lsrK and the newly produced phospho-AI-2 can either be internalized or used to suppress lsrR, an inhibitor of the lsr operon (thereby activating the operon). 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 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.

A first X-ray structure of a receptor (LuxP) was discovered in Vibrio harveyi in 2002, together with its inducer (AI-2), which is one of the few biomolecules containing boron. Autoinducer-2 is conserved among many bacterial species, including Escherichia coli, an enteric bacterium and model organism for Gram negative bacteria. Autoinducer-2 appears to be used for interspecies communication because of this conservation.



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