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Dept. of Oral Biology, Faculty of Dentistry, University of Oslo, PB 1052 Blindern, 0316 Oslo, Norway;
* corresponding author, ascheie{at}odont.uio.no
Abstract (1) Introduction (2) The Biofilm Life Style (2.1) ADAPTATION TO LIFE IN A BIOFILM (2.2) COMMUNICATION IN ORAL BIOFILMS (3) Prospects for Prevention (3.1) SIGNAL TRANSDUCTION INTERFERENCE (3.1.1) Two-component systems (3.1.2) Quorum-sensing (3.2) OTHER STRATEGIES (3.2.1) Surface modification (3.2.2) Replacement therapy (3.2.3) Immunization (4) Concluding Remarks and Future Directions REFERENCES
| Abstract |
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Key words. Oral biofilm, quorum-sensing, two-component signal transduction, histidine kinase, prevention
| (1) Introduction |
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Control of oral biofilms is fundamental to the maintenance of oral health and to the prevention of dental caries, gingivitis, and periodontitis. However, oral biofilms are not easily controlled by mechanical means and represent difficult targets for chemical control (Socransky, 2002). Apart from chlorhexidine and fluorides, only a few of the existing oral prophylactic agents have significant effects (Petersen and Scheie, 1998; Wu and Savitt, 2002; Scheie, 2003). One probable explanation for this low efficacy is the fact that the micro-organisms involved organize into complex biofilm communities with features that differ from those of planktonic cells, whereas micro-organisms have traditionally been studied in a planktonic state. Conclusions drawn from many of these studies, therefore, need to be revalidated. Recent global approaches to the study of microbial gene expression and regulation in non-oral micro-organisms have shed light on two-component and quorum-sensing systems for the transduction of stimuli that allow for coordinated gene expression. Development of novel strategies to prevent and treat diseases caused by oral biofilms might benefit from these recent studies to understand microbial gene expression and regulation in oral biofilms.
| (2) The Biofilm Life Style |
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When organized in biofilms, the micro-organisms are less susceptible to anti-microbials and more resistant to immune defense mechanisms (Mah and O’Toole, 2001; Stewart and Costerton, 2001; Davies, 2003). The concentration of an agent which kills planktonic micro-organisms might have to be increased by 10–1000 times to have the same efficacy on micro-organisms in a biofilm (Lewis, 2001; Mah and O’Toole, 2001; Davies, 2003). This relative resistance to anti-microbial agents partly explains why many oral prophylactic agents predicted to be efficacious in in vitro assays show only marginal clinical effects. Retarded or incomplete penetration of the agent into the biofilm, or reduced growth rate of the micro-organisms due to nutrient limitations, has been considered a reason for lack of efficacy. Another likely explanation is the fact that micro-organisms within a biofilm are physiologically altered due to differential gene expression (Mah and O’Toole, 2001; Lewis, 2001; Davies, 2003).
(2.1) ADAPTATION TO LIFE IN A BIOFILM
Micro-organisms undergo a wide range of physiological and morphological adaptations in response to environmental changes. In biofilms, different gradients of chemicals, nutrients, and oxygen create micro-environments to which micro-organisms must adapt to survive. The perception and processing of chemical information from the environment form a central part of the regulatory control of these adaptive responses. Adaptation to a biofilm life style involves regulation of a vast set of genes, and the micro-organisms are thus able to optimize phenotypic properties for the particular environment. Consequently, biofilm micro-organisms differ phenotypically from their planktonic counterparts. For instance, the enzyme urease in Streptococcus salivarius was found to be differentially regulated during biofilm growth (Li et al., 2000). Also, in Streptococcus mutans, glucosyltransferase and fructosyltransferase genes are differentially expressed in mature biofilm compared with initial biofilms (Burne et al., 1997). Compared with its planktonic counterpart, approximately 20% of the proteins that are expressed in Streptococcus mutans biofilms were shown to be either up- or down-regulated (Svensäter et al., 2001), whereas the level of secreted proteins is altered in biofilms formed by Actinobacillus actinomycetemcomitans (Fletcher et al., 2001). In P. aeruginosa, differences in protein expression as large as 50% were observed between biofilm and planktonic cells and up to 40% between consecutive stages of biofilm development (Sauer et al., 2002).
Biofilm formation is a step-wise process (Fig. 1a
) which commences by adhesion of planktonic micro-organisms to a surface. Further steps involve colonization and co-adhesion, growth and maturation, and finally detachment of some micro-organisms. Evidence is emerging that expression of genes required during the various stages is well-regulated (Davies et al., 1998; Pratt and Kolter, 1999; Sauer et al., 2002; Stoodley et al., 2002).
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). Several such two-component systems exist in Gram-positive and Gram-negative micro-organisms (Dunny and Leonard, 1997; Fabret et al., 1999; Hoch, 2000; Miller and Bassler, 2001). They play important roles in signal transduction and may be essential sensors for adaptation to a biofilm life. Examples of two-component systems involved in biofilm formation include the GacA/GacS in P. aeruginosa (Parkins et al., 2001) and the HK11/RR11 in S. mutans (Li et al., 2002b), as well as the ComD/ComE in S. mutans and S. gordonii (Loo et al., 2000; Li et al., 2001a,b, 2002a; Yoshida and Kuramitsu, 2002).
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) (Fabret et al., 1999; Hoch, 2000). The phosphoryl group is subsequently transferred to a conserved aspartate residue of the regulatory domain of its cognate response regulator. In the most sophisticated systems, activation of the response regulator occurs through multistep phospho-relay cascades. The phosphorylated form of the response regulator will influence transcription by binding to the promoter sequences of genes under its control, resulting in gene activation or repression. Quorum-sensing signaling represents a signaling pathway that is activated as a response to cell density (Dunny and Leonard, 1997; Bassler, 1999; de Kievit and Iglewski, 2000; Miller and Bassler, 2001). Such systems are found in both Gram-positive and Gram-negative micro-organisms. The stimuli of quorum-sensing systems are signal molecules, called autoinducers. The autoinducers are produced at a basal constant level, and the concentration thus is a function of microbial density. Perception of the signal occurs at a concentration threshold. The term "quorum" is used to describe this kind of signal system, since a certain number of micro-organisms must be present for the signal to be sensed and for the population to respond to the signal.
Gram-positive bacteria usually produce oligopeptide signals which are recognized by two-component signal transduction systems (Fig. 3a) (Dunny and Leonard, 1997; de Kievit and Iglewski, 2000). In Gram-negative organisms, the signal molecule belongs to a group of homoserine lactones. These molecules usually diffuse into the cells and bind directly to a response regulator (Fig. 3b) (Bassler, 1999; de Kievit and Iglewski, 2000). As micro-organisms release the signal molecules when approaching a surface, the signal molecule concentration increases in the area between the micro-organism and the surface, due to limited diffusion. The micro-organisms will perceive this concentration increase and thus sense the presence of the surface they are colonizing (Costerton, 1999).
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AI-2 was first found to stimulate bioluminescence in the marine bacterium Vibrio harveyi (Bassler et al., 1994). The role of AI-2 as a density-dependent signal for regulating V. harveyi bioluminescence is now well-established, and evidence for AI-2 signal production by other micro-organisms has been obtained by assessment of their ability to activate the bioluminescence response in V. harveyi (Bassler et al., 1997; Frias et al., 2001; Miller and Bassler, 2001). Evidently, AI-2 signals are released by many micro-organisms, including Gram-positive and Gram-negative species. In V. harveyi, the AI-2 signal molecule is a furanosyl borate di-ester which bears no resemblance to previously characterized bacterial quorum-sensing signals. In most cases, however, the signal molecule involved is unknown (Chen et al., 2002), but its synthesis depends on the luxS gene product (Schauder et al., 2001; Winans and Bassler, 2002). It is not clear whether all AI-2 producers use this molecule as a true quorum-sensing signal. The possibility that AI-2 may represent a metabolic waste product has been raised (Winzer et al., 2002). Further research into the actual nature and function of the AI-2-like molecules in various micro-organisms is therefore needed.
(2.2) COMMUNICATION IN ORAL BIOFILMS
Biofilms are likely to represent a natural scenario for bacterial communication (Davey and O’Toole, 2000; Kolenbrander et al., 2002). The ability to communicate through quorum-sensing has been shown in some oral streptococci and some periodontal pathogens (Table). For most oral biofilm micro-organisms, however, the presence and function of signal transduction pathways and quorum-sensing communication remain to be clarified. Evidence for the involvement of two-component signal transduction systems in oral biofilm formation was first found in Streptococcus gordonii (Loo et al., 2000). Biofilm-formation-deficient S. gordonii mutants resulted from the disruption of comD, which encodes the histidine kinase receptor for the competence stimulating signal peptide (CSP). This quorum-sensing peptide was originally described as an inducer of competence for natural transformation (Håvarstein et al., 1996, 1997). The competent state permits the binding, uptake, and integration of extracellular DNA to occur. It is thought that this system influences the ability of streptococci to adapt to the environment by allowing for the acquisition of new genetic traits from other bacteria. Also in S. mutans, inactivation of the gene encoding the CSP and other competence-related genes, including comC/comE, resulted in biofilm formation deficiency or altered biofilm architecture (Bhagwat et al., 2001; Li et al., 2002a; Yoshida and Kuramitsu, 2002). Although the CSP was first ascribed a role in natural transformation, it has recently been suggested that the main function of the competence system is to sense and elicit responses to environmental stress conditions (Yother et al., 2002). Accordingly, the competence-related signaling system in S. mutans has been related to the ability of these cells to adapt to acidic conditions (Li et al., 2001b).
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), in S. mutans (Wen and Burne, 2002; Merritt et al., 2003), S. gordonii (McNab et al., 2003), P. gingivalis (Chung et al., 2001; Frias et al., 2001; Burgess et al., 2002), and A. actinomycetemcomitans (Fong et al., 2001, 2003). Inactivation of the homologous AI-2 synthase gene in S. mutans (Wen and Burne, 2002; Merritt et al., 2003) and S. gordonii (McNab et al., 2003) did not seem to affect the amount of single-species biofilm. It was recently shown, however, that inactivation of the S. mutans AI-2 synthase gene affected the structure of biofilm when grown in the presence of sucrose (Merritt et al., 2003). In S. gordonii, such mutants show altered expression of genes involved in carbohydrate metabolism. In P. gingivalis, AI-2 deficiency was associated with altered expression of putative virulence genes such as those encoding products involved in hemagglutinin and protease activities (Chung et al., 2001; Burgess et al., 2002). In A. actinomycetemcomitans, AI-2 stimulated leukotoxin production (Fong et al., 2001) and was involved in adaptation to iron limitation (Fong et al., 2001, 2003). This occurred through altered expression of genes encoding various iron transport systems and iron storage proteins. Since the AI-2 response system can be used for interspecies communication, investigation of its role in mixed biofilm communities is of particular interest. It was recently demonstrated, for instance, that in mixed biofilms of S. gordonii and P. gingivalis, inactivation of the AI-2 synthase gene of both strains impaired binding of P. gingivalis to S. gordonii biofilms (McNab et al., 2003).
Bacteriocins might also function as quorum-sensing signals and have a direct effect on biofilm composition. The pre-peptide sequence of the bacteriocin mutacin IV produced by S. mutans (Qi et al., 2001) contains a double glycine-containing leader peptide, suggesting an export and processing pathway similar to that observed for the CSP and other bacteriocins that function as signals in two-component systems. Recently, a link between transformation and bacteriocin production was suggested (Yother et al., 2002). Disruption of S. gordonii genes involved in the early stages of competence development for transformation resulted in mutants deficient in their ability to produce two bacteriocins, STH1 and STH2. This link suggests that killing micro-organisms by bacteriocin could serve dual functions: to liberate DNA for uptake by the competent bacteriocin producers, and to prevent colonization by competing micro-organisms. Sensing of the bacteriocin salivaricin A by S. salivarius probably involves a two-component system comprised of the histidine kinase SalK and the cognate response regulator SalR. Interestingly, S. salivarius can sense the salivaricin A homologue produced by Streptococcus pyogenes (Upton et al., 2001). This clearly illustrates a mechanism of interspecies communication not commonly observed via oligopeptide quorum signals.
| (3) Prospects for Prevention |
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For therapeutic purposes, it is necessary to attack the established biofilm. Therefore, genes essential for viability represent the traditional targets for anti-microbial drug design. Potential agents include, among others, microbial fatty acid biosynthesis inhibitors, bacteriophages, and anti-microbial peptides (Hancock, 1999; Payne et al., 2001; Sulakvelidze and Morris, 2001).
For prophylactic purposes, it seems reasonable to target processes involved in the actual biofilm formation of single- or mixed-bacterial communities that have the potential to cause or favor disease, without perturbing the balance of the normal flora. In this respect, two-component systems and quorum-sensing seem to represent promising future targets. One could envision that interference with such systems in the oral microflora might be used to secure an ecologic balance that promotes the persistence of a healthy flora. The facts that two-component systems are present in most micro-organisms and that signal transduction in mammalian cells is mediated through different mechanisms provide the rationale for using signal transduction systems as targets for prophylactic purposes.
It is likely that the mature oral biofilm is the result of a well-regulated series of processes that could represent potential targets for biofilm control. In the following section, prospects for signal transduction interference and its potential for prophylactic intervention will be discussed. We will also briefly discuss possible strategies for immunization, replacement therapy, and surface modification in view of the novel biofilm concept of dental plaque. Not surprisingly, certain traditional anti-microbial compounds that affect bacterial growth and survival also interfere with bacterial regulatory mechanisms, including the two-component systems. Since their mechanism of action is not specific for two-component systems, they will not be considered here.
(3.1) SIGNAL TRANSDUCTION INTERFERENCE
(3.1.1) Two-component systems
Two-component signal transduction systems and histidine kinases represent potential prophylactic targets (Barrett and Hoch, 1998; Matsushita and Janda, 2002; Stephenson and Hoch, 2002). The histidine kinases and response regulators of the two-component systems exhibit both conserved and variable domains (Fig. 2). This characteristic can be used for the development of inhibitors with species-specific or broad-spectrum activity. The stimulus input domain in the histidine kinases is the most variable, which reflects the wide variety of stimuli or signal molecules that may be sensed by two-component systems. The possibility of interfering with recognition of a stimulus can be achieved by the use of signal analogues, as discussed in the following section for the Gram-positive oligopeptide quorum-sensing system. In this case, the analogues are likely to have a narrow spectrum of activity. Notably, it is not always the fact that inhibition of histidine kinases is sufficient to prevent response regulators from receiving phosphate from other sources. Therefore, the response regulator itself may represent the best target for the inhibition of two-component systems. In most response regulators, conserved and variable residues are found to interact with the histidine kinase. Targeting the conserved residues may therefore interfere with several response regulators in the same organism. Structural similarities of regulators in different microbial species may also allow for the production of cross-species inhibitors based on this principle.
The recent indications that two-component systems are involved in oral streptococcal biofilm formation and acid tolerance (Li et al., 2001b , 2002a,Li et al., b; Loo et al., 2000) support the possibility for interference with oral biofilms through two-component signal transduction.
(3.1.2) Quorum-sensing
The Australian red macro algae Delisea pulchra avoids bacterial colonization through the production of halogenated furanones as secondary metabolites (Givskov et al., 1996). Halogenated furanones are similar in structure to the homoserine lactones that are used as quorum-sensing signal molecules by some Gram-negative micro-organisms. Synthetic halogenated furanones were shown to inhibit homoserine lactone-mediated quorum-sensing and biofilm formation in P. aeruginosa (Hentzer et al., 2002). Initially, furanones were thought to compete with homoserine lactone signal molecules for binding to the transcriptional activator (Gram et al., 1996). More recent evidence, however, suggests that these compounds act by accelerating degradation of the transcriptional regulator that binds to the signal (Manefield et al., 2002). Several systems that disrupt homoserine lactone-mediated quorum-sensing systems are also found in nature, such as those produced by bacillus and variovorax species (Dong et al., 2000, 2001; Leadbetter and Greenberg, 2000).
De-acylation of the signal molecule is another way of interfering with quorum-sensing signaling. Porcine kidney acylase I was recently shown to de-acylate both N-butyryl-homoserine lactone and N-octanoyl-homoserine lactone (Xu et al., 2003), two representatives of homoserine lactone molecules of Gram-negative micro-organisms. The de-acylation resulted in reduced biofilm formation by aquatic micro-organisms. Synthetic signal analogues might also be used to interfere with quorum-sensing. Potent agonists and antagonists of homoserine lactones have been reported (Olsen et al., 2002; Reverchon et al., 2002; Smith et al., 2003). Staphylococcus aureus produces thiolactone oligopeptide signals that act as both activators and inhibitors of quorum-sensing. Naturally occurring truncated forms of the thiolactone peptides may reduce S. aureus virulence (Lyon et al., 2000).
Interestingly, the broad-spectrum anti-microbial bis-phenol triclosan, frequently used in antiseptic soaps and toothpastes, may inhibit the synthesis of precursors of homoserine lactones (Hoang and Schweizer, 1999). The search for homoserine lactone-mediated quorum-sensing, however, has failed to identify this system in oral bacteria (Whittaker et al., 1996; Frias et al., 2001; Burgess et al., 2002). The quorum-sensing systems found in oral bacteria include the AI-2 and streptococcal CSP signaling pathways (Table). As a potential universal quorum-sensing signal used by many Gram-positive and Gram-negative cells, AI-2 may represent an attractive novel target for prophylactic purposes. The finding that AI-2 influences binding of P. gingivalis to S. gordonii biofilms supports the assumption that AI-2 may serve as a communication molecule (McNab et al., 2003). Further elucidation of the role of AI-2 in single- and mixed-bacterial communities is necessary for full appreciation of the AI-2 signaling system as a potential oral prophylactic target.
Interference with the CSP signaling mechanism could provide another way of combatting oral-biofilm-related diseases. The ability of S. gordonii and S. mutans to form biofilms, for instance, could be impaired by inhibiting signal transduction through this system. This pathway should be further explored to ascertain whether early streptococcal colonizers such as Streptococcus oralis, Streptococcus sanguis, and Streptococcus mitis, known to be induced to competence by specific CSPs, also use this communication system for biofilm formation. It would also be interesting to investigate whether the addition of synthetic CSPs interferes with biofilm formation when the required microbial quorum is not present. Such information may be used not only to develop strategies to inactivate the signal or its transmission, but also to favor micro-organisms that can oppose the colonization of more virulent species. Since involvement of most two-component and quorum-sensing systems in biofilm formation seems to depend on environmental conditions, it is important to determine whether such mechanisms are also active under relevant in vivo conditions.
(3.2) OTHER STRATEGIES
(3.2.1) Surface modification
The strategy of surface modification involves altering the tooth surface or the salivary pellicle to impede bacterial colonization (Fig. 1b). It is well-known that the salivary pellicle provides binding sites for the oral bacteria through a complex array of specific and non-specific binding mechanisms. Thus, the composition of the pellicle may modulate bacterial adhesion events. One approach is to change the surface characteristics by manipulating the protein film on the enamel, thereby reducing bacterial adhesion. Several routes of surface modification have been investigated. Functional groups like phosphate and phosphonate may be used to anchor water-soluble, protein-repelling substances to the mineral surface (Olsson, 1998). It has been shown in vitro that the combination of an alkylphosphate and a non-ionic surfactant alters the surface characteristics of the tooth, making it less attractive for micro-organisms. Unfortunately, the clinical efficacy of such coating agents has been low, probably because of difficulties in securing persistent coating with the active component (Olsson, 1998). If these problems are resolved, a future approach to reduce colonization could be to coat the tooth surface with agents that interfere with two-component signal transduction in oral micro-organisms.
(3.2.2) Replacement therapy
Replacement therapy has been suggested as a strategy to replace potential pathogenic micro-organisms with genetically modified organisms that are less virulent (Fig. 1b). The requirements for this type of therapy are, first, that there be a definite pathogen to replace. The replacement organism must not cause disease itself, it must colonize persistently, it must replace the pathogen effectively, and it must possess a high degree of genetic stability. DNA technology has made it possible to produce potential candidates for replacement therapy in caries prevention. Among those is a super-colonizing strain of S. mutans. This strain produces mutacin, which enables it to replace wild-type strains efficiently. It lacks the enzyme lactate dehydrogenase and therefore does not form lactate (Hillman et al., 2000). Other recombinant strains which are ureolytic have also been constructed (Clancy et al., 2000). These strains hydrolyze urea to ammonia, thereby counteracting acidification of the environment.
Animal experiments involving lactate-dehydrogenase-deficient and ureolytic S. mutans strains have shown promising results in caries prevention (Clancy et al., 2000). In the former case, the approach is directed against single microbial species. However, one should not disregard the role of other micro-organisms, such as non-mutans acidogenic streptococci, in the caries process in humans.
A possible future approach is to use genetically modified micro-organisms to deliver tailored molecules that could interfere with adaptive pathways such as two-component signal transduction or quorum-sensing systems. However, one cannot exclude the possibility that a genetically modified replacement strain might later undergo transformation in oral biofilms and then become an opportunistic pathogenic strain.
(3.2.3) Immunization
Immunization against oral diseases—particularly dental caries, but also periodontal disease—has been a central research topic in recent decades (Koga et al., 2002; Smith, 2002). The aim is to inhibit adhesion or reduce the virulence of putative microbial etiologic agents. Several molecules involved in the various stages of both dental caries and periodontal disease pathogenesis would be susceptible to immune intervention and could function as vaccine targets. Micro-organisms could, for instance, be cleared from the oral cavity by antibodies prior to colonization, antibodies could block adhesins or receptors involved in adhesion, or modify metabolically important functions or virulence factors (Fig. 1b). Efforts have been made to immunize both actively and passively. In active immunization, an antigen which will elicit a protective immune response is administered. In passive immunization, the antibody itself is administered.
Animal studies using either active or passive immunization approaches have been successful. There are also data to show that passive immunization in humans impedes recolonization of selected target micro-organisms in both caries (Koga et al., 2002; Smith, 2002) and periodontal disease (Booth et al., 1996). As vehicles for passive immunization, both milk from immunized cows (Shimazaki et al., 2001) and transgenic plants (Ma et al., 1998) have been tested, with encouraging results. Likewise, chimeric recombinant microbial vectors that are avirulent but which express antigens from S. mutans (Huang et al., 2001; Taubman et al., 2001) or P. gingivalis (Sharma et al., 2001) have been shown to provide protection against dental caries and alveolar bone loss, respectively, in experimental animals. However, no vaccination scheme in humans is yet clinically applicable. The question that still needs to be resolved is whether the systemic or the mucosal immune system needs to be stimulated. If an anti-caries vaccine becomes available, it is most likely that it will be administered via the oral route and be based on the induction of the common mucosal immune system. A vaccine against periodontal disease should probably involve both systemic and mucosal immunity.
A major problem is that immunization approaches are generally directed against single bacterial species epitopes, whereas both dental caries and periodontal disease are ecologically driven multi-microbial diseases (Marsh, 1994). Furthermore, since micro-organisms have the ability to form biofilms and to adapt and undergo transformation that may lead to altered antigenicity, it is questionable whether immunization will provide lasting protection.
| (4) Concluding Remarks and Future Directions |
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While the stages of biofilm formation seem to follow basically the same model in various micro-organisms, the biofilm architecture and molecular mechanisms involved in biofilm formation appear to differ. The mechanisms involved in biofilm formation by P. aeruginosa are some of the best-characterized and have served as a model for new hypotheses on mechanisms used by other micro-organisms. Information on the genetic regulation of oral biofilm formation, however, is still lacking. A better understanding of these processes is necessary to the development of novel strategies for oral disease prevention and control based on interference of two-component signal transduction systems or quorum-sensing. Since the systems contain both conserved and variable components, both broad- and narrow-spectrum responses may be available. This could allow for tailoring of prophylactic measures based on individual oral health status and risk assessment.
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) is processed and exported by ABC-transporters. When a threshold level is reached, the extracellular peptides (
) bind to a histidine kinase receptor (HK) in the cell membrane, resulting in autophosphorylation of the histidine phosphotransferase domain. The phosphate (P) is transferred to the cognate response regulator (RR), which can then bind to target DNA and alter gene expression.
)produced by the cells diffuse freely through the cell envelope. When a threshold level is reached, the signal molecules bind to and activate the transcriptional activator (TA). The signal-TA complex binds to target DNA and alters gene expression.