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It Takes Two

December 21, 2012

S. mutansFor psychologists, the human mind is like a computer.  For physicists, the atom is like a solar system.  For biologists, cells are like machines.  But as scientists often remind us, these similes are no more than conceptual placeholders.  The real story – and devil – lies in sorting out the molecular details that unfold according to their own internal and often simile-straining logic.  

A fascinating example of the devil stirring in the details involves the oral bacterium Streptococcus mutans.  Although it can exist in a free-floating form, S. mutans prefers the strength in numbers of living in polymicrobial communities, or biofilms, which form on the surfaces of our teeth.  But to fend off rival bugs that would like to outcompete and fill its ecological niche in the biofilm, S. mutans must perform a number of survival-enhancing tricks.  One is called competence.  The term refers to a bacterium’s ability to import genes from other often-damaged microbes, incorporate them into its DNA, and ostensibly upgrade its capacity to play offense and defense. 

Given S. mutans strong association with tooth decay, scientists wondered how the bacterium shifts into competence mode.  Learning to jam the signal might be helpful in the future to design more efficient strategies to prevent tooth decay.   

Just over a decade ago, researchers seemed to have hit paydirt with the discovery of Competence Stimulating Peptide, or CSP.  They found that S. mutans and many of its fellow streptococci secrete this pheromone like a batch email to alert the members of its strain to import genes.  The CSP likely accumulates in the area of the biofilm occupied by S. mutans , reaches a critical concentration, and begins binding to its cell surface receptor comD.  Like biochemically turning a key in a lock, the binding activates the nearby cytoplasmic protein comE to go forth and stimulate what was much later determined to be the proteins comR and com S.  These proteins then bind to the final domino comX.  The latter promotes the transcription of certain genes needed for competence to commence.  

Quick review:  CSP to comD to comE to comR/S to com X.  Easy and linear enough? Here’s the one curveball.  CSP can activate comE as stated, but the signal will curve in another direction to trigger the transcription of an alternate set of genes involved in producing protective toxins called bacteriocins.  The whys and hows still are unknown.

Two years ago, the alphabet soup grew thicker when scientists discovered another S. mutans-secreted peptide called XIP that triggers competence.  XIP is a 17-residue peptide pheromone that recent work shows is the activated form of the comS protein mentioned above.  It enters cells via a membrane-associated protein and wends its way forward to team with comR, much like its progenitor comS.  The researchers found that the complex of XIP-comR, like a different biochemical key stuck in a somewhat different molecular lock, then activates comX and transcription proceeds apace.  

The XIP finding plunged the machine simile into the devilish details.  It showed that competence is hardwired into S.mutans as a unique two-pronged system linked at comX.  Either prong, or more precisely peptide, can send the competence signal and even perhaps in tandem.  But CSP, while flawless in S. mutans cultures to prompt all bacteria to produce bacteriocins, promotes competence in only about half or less of the cells.  For XIP, the competence cue is more efficient.  Why is an open question. 

But if the system is a mire of details, how does all of this complexity integrate into the clearly defined output of competence?  In the October issue of the journal Molecular Microbiology, NIDCR grantees looked in another direction to provide some overarching conceptual clarity.  They show that the competence system is not an island unto itself.  The two signals are highly sensitive to the environment in which S. mutans finds itself, in this case chemically defined media (all components and their concentrations are predetermined) and complex growth media (includes undefined substances).

Using a single S. mutans strain and exposing it to identical experimental and physical conditions, they found that the peptide signals are qualitatively different in the two media.  In complex media, for example, S. mutans activates comX in response to added CSP.  The activation is restricted, per usual, to a subpopulation of cells, not the entire colony, and highly sensitive to changes in the composition of the media.  But exogenous XIP largely struck out at trying to activate comX in the complex media.  In chemically defined media, the opposite is true.  XIP activates comX, but CSP doesn’t.  

The researchers, after visualizing and further modeling the process in S. mutans, determined CSP needs a working copy of the comS gene in the genome to place its call for competence.  This sets up a bit of a paradox.  While intracellular comS is essential for competence to proceed; extracellular XIP, the activated form of comS, isn’t.   But why?  A possible answer is the two signals encounter different molecular variables within the com system that modulate them differently en route to comX.  Another is feedback.  Once the comR/S button gets punched, a positive feedback loop can occur to keep it locked in the on position.  If correct, competence would come in two modes:  the com R/S feedback loop or the extracellular XIP signal.  The preferred mode of activation would depend on the environmental prompt to confront S. mutans in the oral biofilm, from changes in acidity to rises in oxygen levels.

Looking ahead, the authors concluded, “Future studies will focus on determining how specific environmental factors that influence the homeostasis and pathogenic potential of human oral biofilms impact the behavior of, and virulence expression by, S. mutans at the individual cell level.”


  • Son M, Ahn SJ, Guo Q, Burne RA, and Hagen SJ.  Microfluidic study of competence regulation in Streptococcus mutans:  environmental inputs modulate biomodal and unimodal expression of comX, Mol Microbiol 2012 Oct;86(2):258-72.

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This page last updated: February 26, 2014