Fueling the caries process: carbohydrate metabolism and gene regulation by Streptococcus mutans

Abstract

The nature of the oral cavity and host behaviors has mandated that the oral microbiota evolve mechanisms for coping with environmental fluctuations, especially changes in the type and availability of carbohydrates. In the case of human dental caries, the presence of excess carbohydrates is often responsible for altering the local environment to be more favorable for species associated with the initiation and progression of disease, including Streptococcus mutans. Some of the earliest endeavors to understand how cariogenic species respond to environmental perturbations were carried out using chemostat cultivation, which provides fine control over culture conditions and bacterial behaviors. The development of genome-scale methodologies has allowed for the combination of sophisticated cultivation technologies with genome-level analysis to more thoroughly probe how bacterial pathogens respond to environmental stimuli. Recent investigations in S. mutans and other closely related streptococci have begun to reveal that carbohydrate metabolism can drastically impact pathogenic potential and highlight the important influence that nutrient acquisition has on the success of pathogens; inside and outside of the oral cavity. Collectively, research into pathogenic streptococci, which have evolved in close association with the human host, has begun to unveil the essential nature of careful orchestration of carbohydrate acquisition and catabolism to allow the organisms to persist and, when conditions allow, initiate or worsen disease.

Keywords: biofilms; carbohydrate transport; catabolite repression; dental caries; sugar phosphotransferase system.

Fig. 1

S. mutans has evolved elegant strategies for coping with the diversity and availability of nutrients present within the oral cavity. When a preferred carbohydrate source, such as glucose, is present in abundant quantities, the elevated movement of metabolites through glycolysis profoundly alters many cellular properties. For instance, the kinase activity of the HPr kinase/phosphatase (HprK) is stimulated leading to an increase in the serine-phosphorylated species of HPr [HPr(Ser-P)]. HPr(Ser-P) acts as a co-factor of the major regulator CcpA to repress transcription of metabolic genes containing a catabolite response element (CRE) in their promoter regions, or in the cases of CcpA-independent CCR, directly affects transcription of genes associated with catabolism of non-preferred carbohydrate sources, a process that may also require certain PTS permeases. As the supply of available carbohydrate is diminished, the reduced quantity of readily metabolizable carbohydrate translates to a lower abundance of HPr(Ser-P). Without its co-factor, CcpA no longer functions as a repressor, and with lower levels of carbohydrate transport occurring, PTS porters remain predominately phosphorylated and play a less active role in CCR. Relief of repression by these factors allows for transcription of a variety of genes, including PTS porters, for sensing and accessing a diverse array of carbohydrate sources. Overall, PTS porters monitor the type and levels of carbohydrates present in the oral cavity, while the overall supply of carbohydrate in relation to cellular energy demands is monitored by the activity of HPr and CcpA.

Fig. 2

Illustration of the response of S. mutans and non-cariogenic flora to carbohydrates introduced to the oral cavity.