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J Dent Res 81(6): 380-386, 2002
© 2002 International and American Associations for Dental Research

RESEARCH REPORT
Biological

Inactivation of the Streptococcus mutans fxpC Gene Confers Resistance to Xylitol, a Caries-preventive Natural Carbohydrate Sweetener

H. Benchabane2, L.-A. Lortie1, N.D. Buckley1, L. Trahan1, and M. Frenette1,*

1 Groupe de Recherche en Écologie Buccale, Département de Biochimie et Microbiologie (Sciences) and Faculté de Médecine Dentaire, Université Laval, Quebec City, Quebec, Canada, G1K 7P4; and
2 Samuel Lunenfeld Research Institute, Mount Sinaï Hospital, 600 University Avenue, Toronto, Ontario, Canada, M5G 1X5;

*corresponding author, michel.frenette{at}greb.ulaval.ca


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Xylitol is transported by Streptococcus mutans via a constitutive phosphoenolpyruvate:fructose phosphotransferase system (PTS) composed of a IIABC protein. Spontaneous xylitol-resistant strains are depleted in constitutive fructose-PTS activity, exhibit additional phenotypes, and are associated with the caries-preventive properties of xylitol. Polymerase chain-reactions and chromosome walking were used to clone the fxp operon that codes for the constitutive fructose/xylitol-PTS. The operon contained three open reading frames: fxpA, which coded for a putative regulatory protein of the deoxyribose repressor (DeoR) family, fxpB, which coded for a 1-phosphofructokinase, and fxpC, which coded for a IIABC protein of the fructose-PTS family. Northern blot analysis revealed that these genes were co-transcribed into a 4.4-kb mRNA even in the absence of fructose. Inactivation of the fxpC gene conferred resistance to xylitol, confirming its function. The fxp operon is also present in the genomes of other xylitol-sensitive streptococci, which could explain their sensitivity to xylitol.

KEY WORDS: oral streptococci • dental caries • caries prevention.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Xylitol, a five-carbon natural sugar alcohol, has been shown in clinical trials and laboratory studies to be an effective caries-preventive natural carbohydrate sweetener (Tanzer, 1995). Addition of xylitol to the human diet results in a significant reduction in dental caries (Tanzer, 1995).Sugar substitutes and sweetening additives are used to reduce if not eliminate fermentable carbohydrates in the diet, to disrupt the "sugar/cariogenic bacteria (dental plaque)/susceptible teeth" interactions responsible for caries (Loesche, 1985). Streptococcus mutans and other "low-pH" non-mutans streptococci appear to be of central importance in this pathology (van Houte, 1994). The phosphoenolpyruvate:sugar phosphotransferase system (PTS) is responsible for the transport and phosphorylation of various sugars in numerous bacteria and is a cascade of proteins/enzymes named HPr and Enzyme I (general proteins) and Enzymes II (EII) for the sugar-specific proteins (Postma et al., 1993). The EIIs are composed of IIA, IIB, and IIC domains that are present on one to three polypeptides.

The effect of xylitol on mutans streptococci has been recently reviewed (Trahan, 1995). The growth of mutans streptococci is inhibited in the presence of a combination of dietary sugars and xylitol (Trahan et al., 1996). In xylitol-sensitive (Xs) strains, xylitol is taken up via a constitutive fructose-PTS and is accumulated as non-metabolizable toxic xylitol phosphate in numerous S. mutans strains (Trahan et al., 1985, 1996). The constitutive fructose-PTS is composed of a IIABC protein that phosphorylates fructose on C-6, while the inducible fructose-PTS is composed of IIBC and IIA proteins that generate fructose-1-phosphate (Gauthier et al., 1984). In vitro growth on dietary sugars in the presence of xylitol, or simple xylitol consumption, results in the selective enrichment of naturally occurring xylitol-resistant (Xr) mutants that lack constitutive fructose-PTS activity, are unable to accumulate toxic xylitol phosphate, and are associated with the caries-preventive properties of xylitol (Trahan et al., 1985; Trahan, 1995). To understand the molecular mechanisms involved in the emergence of S. mutans Xr strains, we isolated and characterized the gene coding for the constitutive fructose-PTS of S. mutans.


   MATERIALS & METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Bacterial Strains, Plasmids, and Growth Conditions
Streptococcus mutans 123.1 (Vadeboncoeur and Trahan, 1983) was used as the wild-type strain and was grown at 37°C in aerobic conditions in TYE medium (Buckley et al., 1999) supplemented with 0.2% (w/v) glucose. E. coli XL1-Blue was grown at 37°C with agitation in Luria-Bertani broth (LB) supplemented with 10 µg/mL tetracycline. When E. coli XL1-Blue was transformed by pUC18 or recombinant plasmids, a 50µg/mL quantity of ampicillin was added to the medium. E. coli XL1-Blue bearing the p517spec and p517spec{delta}bla plasmids was grown in LB medium supplemented with 100 µg/mL spectinomycin. S. mutans NDBX-10 was grown in TYE supplemented with 0.2% (w/v) glucose and 600 µg/mL spectinomycin.

DNA and RNA Manipulations
Unless otherwise mentioned, all DNA and RNA manipulations were performed according to standard procedures (Ausubel et al., 1990). DNA sequencing was performed by the DNA sequencing service of Université Laval. Computer-assisted DNA and protein analyses were performed with the use of the Genetics Computer Group Sequence Analysis software package Version 9.1 (Devereux et al., 1984). S. mutans 123.1 DNA was extracted as described by Lortie et al. (1994). A fragment of the fxpC gene was PCR-amplified with Taq DNA polymerase (Cetus) with use of the degenerated oligonucleotides TG(T/C)CCIAC(A/T)GGIAT(C/T)GCICA(T/C)AC(A/T)TT(T/C)ATGG) and AIGC(T/A/G)GC(C/T)TT(A/G)TT(A/T)ACIGGICC ICCCAT(A/G)TC, and the resulting amplicon was used as a probe for Southern and Northern blots.

Inactivation of fxpC in Streptococcus mutans 123.1
The p517 plasmid bearing a MfeI fragment containing the 3' -ends of fxpA and fxpB and a 1104-bp fragment of fxpC was digested with StyI and BsrGI and Klenow-treated (Ausubel et al., 1990). The Klenow EcoRI–HindIII fragment containing a spectinomycin-resistance gene from spc-pGEM7Zf(–) (Buckley et al., 1995) was ligated to the digested p517, generating the p517spc plasmid, which was digested with PvuI to excise a portion of the bla and lacZ genes. The resulting plasmid (p517spc{delta}bla) was used to transform electrocompetent S. mutans 123.1 as per Buckley et al. (1999). One of the spectinomycin-resistant clones (NDBX-10) was selected for further study. The xylitol-sensitivity was assessed as described previously (Trahan et al., 1996).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Analysis of the fxp Operon
PCR and chromosome walking were used to isolate the fxp operon that codes for the constitutive fructose/xylitol-PTS. Analysis of the nucleotide sequence of the fxp operon suggested that it was composed of three open reading frames (ORFs) (Figs. 1, 2AGoGo). A promoter sharing a perfect consensus sequence with canonical promoters was found 28 bp upstream from the ORF1 initiation codon. A 10-bp perfect direct repeat (TTTGGTAGAA) was found 5 bp upstream from the –35-promoter sequence. A CRE (Catabolite Responsive Element) sequence in perfect concordance with the consensus sequence TGWAAN CGNTNWCA (Weickert and Chambliss, 1990) was found 6 bp downstream from the -10-promoter sequence. Comparison of the fxp operon with microbial genome databases (Fig. 2BGo) revealed the presence of fxp-like operons composed of three ORFs in Streptococcus pyogenes, Streptococcus pneumoniae, and Streptococcus equi. Promoters that were identical or quasi-identical to the S. mutans fxp promoter were present in the 5'-region of these operons (Fig. 2BGo). Consensus CRE sequences were also present between the -10-hexamers and the beginning of the genes coding for FxpA orthologs. Furthermore, from 8- to 12bp direct repeats with 1 to 3 mismatches were present 5 to 8 bp upstream from the -35-boxes of the fxp promoters.




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  		Figure 1. Nucleotide and inferred amino acid sequences of the fxp operon and of part of the contiguous genes from Streptococcus mutans 123.1 (accession #AF395874). Translation initiation sites of the open reading frames are shown. The -10 and -35 promoter regions are indicated by double underlining, and converging arrows illustrate transcriptional terminators. The CRE site and the direct repeat are shown by lightly shaded boxes. The protein regions corresponding to the DeoR family signature of FxpA, the PfkB family of carbohydrate kinases signatures of FxpB, and the IICFru signature of FxpC are shadowed in black. The phosphorylated residues of the IIA and IIB domains of FxpC are boxed in gray. The putative substrate interacting sequence of FxpC is shadowed in gray.

 


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  		Figure 2. (A) Schematic representation of the S. mutans fxp operon. (B) Comparison of the promoter regions of fxp operons from Streptococcus mutans (Smu), Streptococcus pneumoniae (Spn), Streptococcus pyogenes (Spy), and Streptococcus equi (Seq). The -35, -10, and CRE regions are boxed. The beginning of fxpA and the direct repeats are indicated. Underlined nucleotides correspond to direct repeats in the promoter regions.

 
In S. mutans, the ORF located upstream from the fxp operon had significant levels of identity with genes coding for thioredoxin reductases. A terminator was found in the intercistronic region between the operon and the incomplete ORF located downstream from this stemloop. The ORF shared a high level of identity with genes coding for homocysteine methyltransferases. The translation initiation codon for the first ORF of the fxp operon (FxpA) could be GUG or, alternatively, the fourth codon (AUU), which represents a rare initiation codon (Pon et al., 1989). In silico structure prediction suggested that FxpA contained a helix-turn-helix DNA binding motif (Fig. 1Go). Database sequence analyses revealed that FxpA shared identity with several members of the DeoR (repressor of the deoxyribose operon) family of regulators and contained the DeoR regulator family signature motif, RXXX(L/I/V/M) XXX(L/I/V/M)-17X-(S/T/A)XXT(L/I/V/M/A) R(K/R/N/A)D(L/I/V/M/F) (Schweizer and Po, 1996).

A database search revealed that FxpB, the polypeptide encoded for by the second ORF, shared high levels of identity with various orthologs from S. pyogenes (77%), S. pneumoniae (75%), and S. equi (67%). Interestingly, the genes coding for the FxpB orthologs are located immediately downstream from the genes coding for the FxpA orthologs in each of the genomes. FxpB also shared high levels of identity with several eubacterial 6-phospho and 1-phosphofructokinases. A search of the S. mutans genome for homology revealed the presence of two other genes that shared significant levels of identity with the product of fxpB , i.e., fruK, which codes for a phosphofructokinase (36% identity) in the inducible fructose-PTS operon (Lemay, 1996) and lacC, which codes for a tagatose 6-phosphate kinase (32% identity) (Rosey and Stewart, 1992). The method of Belouski et al. (1998) was used to analyze the phosphofructokinase activities of an E. coli strain that overproduced FxpB. The 1-phosphofructokinase activity in this strain increased 97-fold after IPTG induction, confirming the nature of the enzymatic activity of FxpB (result not shown).

The FxpC polypeptide, coded for by the third ORF, shared high levels of identity with EIIFru from unfinished streptococcal and enterococcal genomes: 68% identity with an ORF from S. pyogenes, 67% with an ORF from S. pneumoniae, 61% with an ORF from S. equi, and 56% with an ORF from Enterococcus faecalis. These are IIABC orthologs except for the one from S. equi, which is a IIBC. All these ORFs are located downstream from genes coding for FxpB orthologs and should be part of operons that have the same organization as fxp. Analysis of the unfinished S. mutans genome revealed the presence of another fructose-PTS EII that corresponded to the IIBC and IIA domains of the inducible fructose-PTS (Lemay, 1996). FxpC was aligned with the IIA, IIB, and IIC domains of other IIFru and IIFru-like proteins. A comparison of the IIA domain of FxpC with the other IIAFru domains revealed the presence of a phosphorylated histidine at position 67. A signature sequence containing this phosphorylated residue (GXXXXXPHG) has been proposed by Reizer et al. (1994). However, the IIAFru coded for by fxpC did not possess the last G residue of this sequence.

Interestingly, FxpC did not have the duplicated IIB' domains previously described for other EIIFru. A comparison of IIB domains revealed high levels of identity among residues surrounding the putative IIB phosphorylation site located at cysteine-175 of FxpC (Fig. 1Go). Reizer et al. (1995) have proposed a signature sequence for fructose IIC-like family members [DMGGP(L/I/V/M)NKXA] that is conserved in the IICFru domain of FxpC (Fig. 1Go). A conserved FISE motif involved in substrate binding has been identified in a large cytoplasmic loop of IICFru domains (Lengeler et al., 1994). A FITE sequence is present in FxpC at the corresponding site. The Ser-Thr modification could be regarded as conservative due to the presence of a hydroxyl function on both amino acids in the lateral chain. Interestingly, this motif partially overlaps the first phosphokinase consensus sequence (de Crécy-Lagard et al., 1991).

Transcription Analysis
Northern blot analysis of total RNA from S. mutans grown in the presence of glucose, a carbohydrate that is not the substrate of FxpC, revealed the presence of a 4.4Kb transcript that hybridized with the fxpC-specific probe (Fig. 3Go). The size of the transcript corresponded to that of the fxp operon transcript originating from the promoter located upstream from fxpA and ending at the terminator downstream from fxpC. Northern blot analysis with trxB and metE as probes confirmed that these genes were not co-transcribed with the fxp operon (result not shown).



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  		Figure 3. Northern blot of total RNA from S. mutans 123.1 grown in TYE glucose medium with a fragment of fxpC as a probe. The arrow indicates the 4.4-kb fxp operon transcripts.

 
Inactivation of fxpC and Resistance to Xylitol
The fxpC ORF was interrupted by allelic exchange with p517spc{delta}bla. Southern hybridization analysis confirmed the integration of the spc gene in fxpC by double crossover and the elimination of pUC18 from the transformants (data not shown). The xylitol sensitivity of the transformants was compared with that of the wild-type strain. As previously reported (Vadeboncoeur and Trahan, 1983), S. mutans XS is highly susceptible to the growth-inhibitory effects of xylitol, with a 2.2-fold increase in generation time in the presence of the pentitol (TableGo). The fxpC-defective mutant was completely resistant to xylitol, and no differences were seen in generation times in the presence or absence of xylitol.


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  		Table. Mean Generation Times of Streptococcus mutans 123.1 and NDBX-10 Grown in Glucose With or Without Xylitola
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Xylitol has been successfully used as a sugar substitute in the fight against dental caries (Tanzer, 1995). However, the addition of this pentitol to the human diet gives rise to xylitol-resistant (Xr) strains of S. mutans. In addition to the lack of constitutive fructose-PTS activity (Gauthier et al., 1984), Xr strains exhibit a plethora of phenotypic alterations. To gain a better understanding of the molecular mechanisms underlying these modifications, we isolated the genes coding for the phosphoenolpyruvate:fructose/xylitol phosphotransferase system that is primarily involved in xylitol resistance.

The sequence of the fxp promoter perfectly matched the sequence of canonical promoters. The –35 hexamer is preceded by a 10-bp direct repeat that may play a role in binding a trans-acting factor. Ten-base-pair direct repeats are also present in the promoters of the S. aureus and S. mutans lac operons and have been proposed as DNA-binding sites for LacR. Another feature of the fxp promoter is the presence of a CRE site between the putative -10 box and the initiation codon of the first gene. The location of the CRE sequence suggests a mechanism involving transcription repression (Hueck and Hillen, 1995). Given that the fructose/xylitol-PTS is constitutive, the regulatory function could serve to decrease the production of IIABCFru/Xyl when the concentration of the carbon source is too high, a mechanism that has been previously reported (Ye and Saier, 1996). All these features are shared by fxp promoters in the genomes of several other streptococci, suggesting that these operons may have similar regulatory mechanisms.

The first gene of the fxp operon (fxpA) codes for a repressor-type regulator of the DeoR family (Mortensen et al., 1989). The absence of an ATG initiation codon suggests that very small quantities of FxpA may be present in the cytoplasm. This feature may be shared by FxpA orthologs from S. pneumoniae, S. pyogenes, and S. equi, which also lack standard initiation codons (Fig. 2Go). The precise role of FxpA in the expression of the fxp operon and its DNA target remains to be determined.

The second gene of the operon (fxpB) codes for a 1-phosphofructokinase. Postma et al. (1993) have reported that the genes coding for enzymes responsible for the catabolism of the sugars transported by the PTS are frequently co-transcribed with those coding for EIIs, while Gauthier et al. (1984) have reported that the constitutive fructose/xylitol-PTS generates fructose-6-phosphate. S. mutans strains with two fructose-PTS that phosphorylate fructose at two different positions (Gauthier et al., 1984) require both 1- and 6-phosphofructokinase. A search of the S. mutans genome identified an additional putative phosphofructokinase gene (fruK) that is part of the operon that codes for the inducible fructose-PTS (Lemay, 1996). However, the phosphofructokinase activity of FruK remains to be determined.

The third gene of the operon (fxpC) coded for a IIABCFru. Transcriptional analysis revealed the presence of a 4.4-Kb transcript originating from the promoter located upstream from fxpA and ending at the terminator located downstream from fxpC. A Northern blot was performed with DNA from cells grown in the presence of glucose, a sugar that is not a substrate of the fructose/xylitol-PTS (Gauthier et al., 1984), confirming that the expression of the fxp operon is constitutive. Inactivation of fxpC rendered the resulting strain resistant to the toxic effect of xylitol, a result that confirms the physiological data suggesting that Xr strains lack the constitutive fructose/xylitol-PTS (Gauthier et al., 1984; Trahan et al., 1985) and also confirms the original hypothesis that fxpC codes for the xylitol-transporting IIABC protein. We are currently looking at whether inactivating fxpC or interfering with the fxp operon will result in the in vivo appearance of Xr strains. Another interesting finding is the presence of fxp operons in the genomes of other streptococci, including S. pneumoniae. This species has been reported to be one of the etiological agents of acute otitis in children (Kontiokari et al., 1995). Various studies have reported that chewing gums containing xylitol have a protective effect with respect to this pathology, while Uhari et al. (1996) have shown that the growth of S. pneumoniae is inhibited by this pentitol. It would be interesting to determine the functionality of the fxp operon in this species and its involvement in xylitol sensitivity.


   ACKNOWLEDGMENTS
 
This work was supported by the Canadian Institutes of Health Research (grants MT11276 and 12077), National Science and Engineering Research Council of Canada (scholarship for H.B.), and Fonds Formation de Chercheurs et Aide à la Recherche (team support grant). A preliminary report was presented at the 1997 IADR General Session in Orlando, Florida, J Dent Res 76(IADR Abstracts):103 (abstract #714).

Addendum

During the editorial process, further work has confirmed that xylitol is transported by the IIABCFru in S. mutans (Wen et al., 2001).

Received July 20, 2001; Last revision March 27, 2002; Accepted April 18, 2002


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 DISCUSSION
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