Bacteriocins are naturally-occurring antibiotic peptides produced by Gram-positive bacteria; they are usually small (e.g. 24 amino acids). Some bacteriocins are lantibiotics, which is to say that they are post-translationally modified so as to encompass the amino acid lanthionine or 'Lan'.This amino acid is formed when wool is mildly treated with alkali, hence an association exists with the familiar lanalin. The gene name 'lan' is often applied to genetic sequences encoding the precursor bacteriocin or associated modification and transport elements. A large review of lantibiotic-production has been recently published [1].

Bacteriocins discovered in some strains of Streptococcus mutans have been given the name mutacins and the gene name 'mut. These should not be confused with mutator-related elements whose genes are also designated 'mut'. In some S.mutans strains, mutacin-related proteins become implicated in competence and may be designated 'com'.

Five groups of mutacins, I - V, have been reported in S. mutans on the basis of gene sequences. Groups I-III are encoded in well-characterized operons that generate lantibiotics. IV and V operons are much smaller and may be more involved in competence [9]. A bacteriocin operon has been recently reported from S.mutans strain GS5 that is dissimilar in organization and sequence from the prototypical MutI and III operons; it shows some partial similarity to one mut II sequence and is a likely lantibiotic; its gene designations are 'smb'.[2,3 ]. Strains producing bacteriocins have been categorized into 24 groups by Morency et al. [13 cited by 7].

The diversity of bacteriocins (or mutacins) may have ramifications for pathogenesis, hence studies of correlation with mutans-caused tooth caries are ongoing and companies are evaluating different bacteriocins for their potential as drugs, specifically designer drugs. Balakrishnan and colleagues placed a number of mutacins into four groups on the basis of phenetic properties [6]. Members of the same group can be immune to one another, as to be expected; immunity then becomes a different way to analyze bacteriocins.

Some strains, such as the UA159 represented in this database, do not appear to be typical lantibiotic producers but may have some immunity and may effect toxicity through MutIV genes named nlmA and nlmB (9). These (Smu0133 and Smu0134) and their paralogs in UA159 are reported to be under the regulation of the competence system (15). Furthermore, UA159 possesses a partial operon -- 5 of 9 genes -- found in the Scn bacteriocin operon of Strep pyogenes [8]; it also has weak similarity to some mutacin immunity genes reported to date. No significant similarity has been shown to the Smb sequences. Two relevant genomic islands have been proposed by ORALGEN staff for S. mutans, one encompassing the Scn genes, the other encompassing some bacitracin-like genes (see GENETIC ISLANDS), suggesting that these genes have arisen in UA159 through horizontal transfer.

BLAST studies and alignments reveal that Mut I and Mut III sequences are sufficienctly similar to have arisen from a common lineage. Indeed, with the same operon organization and virtually identical A, A' and B gene sequences, what exactly distinguishes them?

The SmbM1 and T8 (mut II) orf1 and, to a lesser extent the MutM, sequences have some weak similarity but their A and B sequences and operon organization are too different to consider them related. Many known bacteriocins have yet to be sequenced.

In light of the limited representation of bacteriocin operons in this database, records MI0001 - MI0015, MII0001 - MII0007, MIII0001 - MIII0008 and SMB0001- SMB0007 have been added for the MutI, MutII, MutIII and Smb producing organisms. The operon organizations known to-date in S.mutans (and for comparison in S.pyogenes) are summarized in Fig. 1 along with the A gene sequences (Fig. 2). Table I constitutes a glossary of sorts for the S.mutans bacteriocin genes characterized to-date.

FIGURE 1: Operon Organization for S.mutans bacteriocin genes from five strains; shown for comparison is the Scn cluster from Strep. pyogenes.

   MUT I :   R - A - A' - B - C - D - P - T - F -E - G - orfX - orfY - orfZ - orfR (UA140 and CH43)

   MUT II :      A - M - T - F - E - G - fba (T8)

   MUT III : R - A - A' - B - C - D - P -T (UA787)

   SMB:      M1 - F - T - M2 - G - A - B (GS5)

   UA159:    G - E - F - ... -K - R (residues 1048, 1647-1649, 1652-1653)

   Scn:  K - R - A - A1 - M - T - F - E - G (S.pyo strain FF22)

FIGURE 2: A Gene Sequences ( pre-modification bacteriocin)

SMB :     MKSNLLKINNVTEMEKNMVTLIKDEDMLAGGSTPACAIGVVGITVAVTGISTACTSRCINK  (GS5)

Mut I:    MSNTQLLEVLGTETFDVQEDLFAFDTTDTTIVASNDDPDTRFSSLSLCSLGCTGVKNPSFNSYCC  (UA140  AND CH43)
 
Mut II:   MNKLNSNAVVSLNEVSDSELDTILGGNRWWQGVVPTVSYECRMN (T8)

Mut III : MSNTQLLEVLGTETFDVQEDLFAFDTTDTTIVASNDDPDTRFSSLSLCSLGCTGVKNPSFNSYCC  (UA787)

ScnA:     MEKNNEVINSIQEVSLEELDQIIGAGKNGVFKTISHECHLNTWA (S. pyo FF22)

GLOSSARY:

mutR	-	transcriptional regulator similar in strains I, II and III and similar to regulators in other bacteria (e.g. strep pneumoniae)
mutA	-	primary coding sequence for the precuror peptide for the mutacin/bacteriocin
mutA'	-	function unknown, reported to not be necessary for bacteriocin production; sequence conserved in Mut I and III sequences
mutB	-	a modifying enzyme in MutI, a precursor along with the A precursor in Smb
mutC	-	modifying enzyme, affecting post-translational modification of A
mutD	-	modifying enzyme thought to effect C-terminal oxidative decarboxylation
mutP	-	protease
mutT	-	ABC related transporter
mutF	-	ABC related transporter similar in MutI, MutII, MutIII and Smb
mutE	-	ABC element
mutG	-	ABC element similar across many strains
SmbM1	-	modifying enzyme for proSmb from strain GS5
SmbM2	-	modifying enzyme for proSmb from strain GS5

The ORALGEN database records give preference to the gene name 'lan' rather than 'mut' to avoid confusion with mutator genes.

Selected bacteriocin references:

1. Chatterjee,C., Paul M., Xie, L., and van der Donk, W.A.
Biosynthesis and mode of action of lantibiotics.
Chem Rev. 2005, 105:633-683
PMID

2:  Wang BY, Kuramitsu HK. 
 Interactions between oral bacteria: inhibition of Streptococcus mutans
bacteriocin production by Streptococcus gordonii.
Appl Environ Microbiol. 2005 Jan;71(1):354-62. 
PMID: 15640209 [PubMed - indexed for MEDLINE]

3. Yonezawa H, Kuramitsu HK.
Genetic analysis of a unique bacteriocin, Smb, produced by Streptococcus mutans GS5.
Antimicrob Agents Chemother. 2005 Feb;49(2):541-8.
PMID: 15673730 

4:  Qi F, Merritt J, Lux R, Shi W. 
 Inactivation of the ciaH Gene in Streptococcus mutans diminishes mutacin
production and competence development, alters sucrose-dependent biofilm
formation, and reduces stress tolerance.
Infect Immun. 2004 Aug;72(8):4895-9. 
PMID: 15271957 [PubMed - indexed for MEDLINE]

5:  Hale JD, Balakrishnan B, Tagg JR. 
 Genetic basis for mutacin N and of its relationship to mutacin I.
Indian J Med Res. 2004 May;119 Suppl:247-51. 
PMID: 15232205 [PubMed - indexed for MEDLINE]

6:  Balakrishnan M, Simmonds RS, Kilian M, Tagg JR. 
 Different bacteriocin activities of Streptococcus mutans reflect distinct
phylogenetic lineages.
J Med Microbiol. 2002 Nov;51(11):941-8. 
PMID: 12448678 [PubMed - indexed for MEDLINE]

7:  Bekal-Si Ali S, Hurtubise Y, Lavoie MC, LaPointe G. 
 Diversity of Streptococcus mutans bacteriocins as confirmed by DNA analysis
using specific molecular probes.
Gene. 2002 Jan 23;283(1-2):125-31. 
PMID: 11867219 [PubMed - indexed for MEDLINE]

8. Adjic, D,  McShan, WM, McLaughlin RE, et al. 
Genome sequence of Streptococcus mutans UA159, a cariogenic dental pathogen
Proc. Natl. Acad. Sci. USA 99:14434-14439

9:  Qi F, Chen P, Caufield PW. 
 The group I strain of Streptococcus mutans, UA140, produces both the
lantibiotic mutacin I and a nonlantibiotic bacteriocin, mutacin IV.
Appl Environ Microbiol. 2001 Jan;67(1):15-21. 
PMID: 11133423 [PubMed - indexed for MEDLINE]

10:  Balakrishnan M, Simmonds RS, Tagg JR. 
 Diverse activity spectra of bacteriocin-like inhibitory substances having
activity against mutans streptococci.
Caries Res. 2001 Jan-Feb;35(1):75-80. 
PMID: 11125201 [PubMed - indexed for MEDLINE]

11:  Qi F, Chen P, Caufield PW. 
 Purification and biochemical characterization of mutacin I from the group I
strain of Streptococcus mutans, CH43, and genetic analysis of mutacin I
biosynthesis genes.
Appl Environ Microbiol. 2000 Aug;66(8):3221-9. 
PMID: 10919773 [PubMed - indexed for MEDLINE]

12. Qi F., Chen, P., and Caufield, P.W.
Purification of mutacin III from Group III Streptococcus mutans UA787 and genetic analyses of mutacin III biosynthesis genes.
Appl Env. Microbiol 65: 3880-3887
PMID: PMID: 10473390

13.Morency, H., Trahan, L., Lavoie, M.C., 
Preliminary grouping of mutacins.
Can.J.Microbiol. 1995 41: 826-831

14. Chikindas ML, Novak J, Driessen AJ, Konings WN, Schilling KM, Caufield PW.
Mutacin II, a bactericidal antibiotic from Streptococcus mutans.
Antimicrob Agents Chemother. 1995 Dec;39(12):2656-60.
PMID: 8592997

15. Kreth J, Merritt J, Shi W, Qi F. 
Co-ordinated bacteriocin production and competence development: a possible mechanism for taking up DNA from neighbouring species. 
Mol Microbiol. 2005 Jul;57(2):392-404. 
PMID: 15978073