Bacteria Can Talk! (and now we can silence them)

Most cellular biology has focused on eukaryotes, but just as interesting are the prokaryotic bacteria. As the most ancient life form, bacteria have primitive features and are characterized as single celled organisms. Presumed to be asocial and reclusive, bacteria were once thought to lack cell to cell communication systems. Evidence of cell-cell communication was discovered in the marine bacterium Vibrio fischeri (Nealson & Hasting 1979). In dilute concentrations, Vibrio did not bioluminesce, but when the bacteria density was sufficient, secreted chemical signals reached neighboring cells and triggered bioluminescence.

Quorum sensing was first detected in the bioluminescent Vibrio fischeri.

The mechanism involves the production, then release, and finally adherence to receptors of hormorne-like molecules called autoinducers (see figure 1). Termed quorum sensing, this intra and inter-species communication blurs the definition of multicellularity (Waters & Bassler 2005). Quorum sensing can occur through species-specific autoinducers or through general broadcast autoinducers shared by many species. The interplay between autoinducers and their receptors controls gene expression and ultimately the synchronized behavior in bacterial populations.

Figure 1: Autoinducers (red triangles) are produced by LuxI synthase. When concentration of autoinducer is sufficient, it binds to the LuxR receptor, initiating the light producing reaction. From Waters & Bassler 2005.

Quorum sensing circuits are responsible for virulence gene activation in many pathogens. Knowing this, a novel antibiotic concept has been developed which utilizes antagonists to jam the receptors and prevent the expression of virulence genes in a bacterial population. The autoinducers used by gram-negative bacteria are usually acyl-homoserine lactone molecules(AHLs) (Chen et al 2011). Numerous pathogenic bacteria are known to use the LuxR protein family quorum sensing mechanism shown above to detect the AHLs (Fig 1). Previous work has identified several quorum-sensing antagonists, but their mechanism had previously remained a mystery.

Chen et al. studied the antagonist mechanism used in blocking the AHL:LuxR complex in the human pathogen Chromobacterium violaceum. Using a variety of methods from genetics to x-ray crystallography, the researchers characterized the LuxR type protein CviR. Without an autoinducer the proteins are unstable, but a stable complex is formed when the autoinducer is present (see Figure 2). In the stable form, virulence genes are activated. Chen et al. show that it is possible to develop antagonists that function by stabilizing transient interdomain interactions, giving rise to an inactive configuration (Chen et al. 2011). Essentially, the antagonist blocks the autoinducers by binding in its place, rendering the site inactive. Such a system worked as long as the antagonist induced a closed conformation, which is unable to bind to the DNA domain. Future research is being conducted to identify molecules that preferentially bind in place of the autoinducer and that favor an inactivating interaction. These new molecules may lead to the application of anti-quorum sensing molecules to therapeutic antibiotics.

Figure 2: The two monomers are colored orange and blue. Each monomer of two domains, a ligand-binding domain (LBD) and a DNA-binding domain (DBD). The antagonist induced a closed conformation, so the CviR is unable to bind to the DNA domain.

In a period when the development of antibiotics is declining and the number of antibiotic resistant bacteria is on the rise, advancements in the field of quorum sensing have promising application. The autoinducers are both species specific and generic, so particular pathogenic bacteria can be targeted through this type of antibiotic. Intuitively one could also create a pro-quorum sensing molecule to increase the function of beneficial bacteria. Now that scientists have cracked the code, we are on our way to ending bad communication.

Works Cited:

G. Chen, LR Swem, DL Swem, DL Stauff, CT O’Loughlin, PD Jeffrey, BL Bassler, FM Hughson. (2011) A Strategy for Antagonizing Quorum Sensing. Molecular Cell 42, 199–209.

CM Waters & BL Bassler. (2005) Quorum Sensing: Cell-to-Cell Communication in Bacteria. Annu. Rev. Cell Dev. Biol. 21:319–46.

KH Nealson & JW Hastings (1979). Bacterial Bioluminesence: Its Control and Ecological Significance. Microbiiological Reviews 43:496-518.

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