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Antimicrobial Agents and Chemotherapy, May 2001, p. 1323-1336, Vol. 45, No. 5
Department of Bacteriology, Juntendo
University, Tokyo 113-8421, Japan
Received 19 September 2000/Returned for modification 26 December
2000/Accepted 9 February 2001
The SCCmec is a mobile genetic element characterized by the
presence of terminal inverted and direct repeats, a set of
site-specific recombinase genes (ccrA and ccrB),
and the mecA gene complex (14, 17). The element
is precisely excised from the chromosome of N315 and integrates site
and orientation specifically into an S. aureus chromosome
through the function of a unique set of recombinase genes,
ccrA and ccrB. SCCmec was distributed
widely in Japanese MRSA strains isolated in the 1990s
(11). However, most of the MRSA strains isolated in other
countries did not possess SCCmec, as judged by dot-blot
hybridization of extracted chromosomal DNA with probes covering various
parts of the SCCmec of N315. By cloning and nucleotide
sequence determination of the DNA region surrounding the
mecA gene from two representative MRSA strains, NCTC 10442 (the first MRSA isolate in England in 1961) and 85/2082 (the 1985 isolate in New Zealand), we found two novel genetic elements that shared similar structural features of SCCmec. We designated
them type I (NCTC 10442) and type III (85/2082) SCCmec, and
we designated that of N315 type II SCCmec in the order of
the year of isolation of the strains. Here, we report a detailed
structural comparison of the three types of SCCmec.
Bacterial strains and media.
All of the MRSA or pre-MRSA
strains used in this study are listed in Table
1. Pre-MRSA, represented by N315, is an
S. aureus strain that has a mecA gene, but is
susceptible to methicillin because of a strong repression of
mecA gene transcription exerted by mecI-encoded
repressor function (18). Two strains, ATCC 25923 isolated
in 1945 and NCTC 8325 (a kind gift from B. Berger-Bachi), were used as
methicillin-susceptible S. aureus (MSSA) standard strains.
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.5.1323-1336.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Structural Comparison of Three Types of Staphylococcal Cassette
Chromosome mec Integrated in the Chromosome in
Methicillin-Resistant Staphylococcus aureus
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
-lactam resistance gene mecA of
Staphylococcus aureus is carried by a novel mobile genetic
element, designated staphylococcal cassette chromosome mec
(SCCmec), identified in the chromosome of a Japanese
methicillin-resistant S. aureus (MRSA) strain. We now
report identification of two additional types of
mecA-carrying genetic elements found in the MRSA strains
isolated in other countries of the world. There were substantial
differences in the size and nucleotide sequences between the elements
and the SCCmec. However, new elements shared the
chromosomal integration site with the SCCmec. Structural
analysis of the new elements revealed that they possessed all of the
salient features of the SCCmec: conserved terminal inverted
repeats and direct repeats at the integration junction points,
conserved genetic organization around the mecA gene, and
the presence of cassette chromosome recombinase (ccr) genes
responsible for the movements of SCCmec. The elements,
therefore, were considered to comprise the SCCmec family of
staphylococcal mobile genetic elements together with the previously
identified SCCmec. Among 38 epidemic MRSA strains isolated
in 20 countries, 34 were shown to possess one of the three typical
SCCmec elements on the chromosome. Our findings indicated
that there are at least three distinct MRSA clones in the world with
different types of SCCmec in their chromosome.
INTRODUCTION
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
-Lactam resistance of
methicillin-resistant Staphylococcus aureus (MRSA) is
determined by the function of penicillin-binding protein 2' (PBP2')
encoded by the methicillin resistance gene mecA (20,
29). PBP2' binds to -lactam antibiotics with much lower
affinity than the intrinsic set of PBPs of S. aureus do (7, 23, 35). By nucleotide sequence determination of an MRSA-specific chromosomal region of strain N315 (isolated in Japan in
1982), we have found that the mecA gene is carried by a
novel genetic element, designated staphylococcal cassette chromosome mec (SCCmec), inserted into the chromosome
(14, 17).
MATERIALS AND METHODS
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
TABLE 1.
Characteristics of 38 MRSA strains isolated worldwide
, were prepared according to the method of Sambrook et al. (25). Heart infusion agar,
heart infusion broth, brain heart infusion (BHI) broth, and BHI agar (Eiken Kagaku, Co., Ltd., Japan) were used for cultivation of S. aureus.
The following antibiotics were freshly prepared and used at the
indicated concentrations: ampicillin (Meiji Seika Co., Tokyo, Japan),
100 µg/ml; tetracycline (Sigma Co., St. Louis, Mo.), 10 µg/ml;
latamoxef (Shionogi Pharmacy Co., Osaka, Japan), 15 µg/ml; ceftizoxime (Fujisawa Pharmacy Co., Osaka, Japan), 25 µg/ml.
Cloning and determination of the nucleotide sequence of the SCCmec of NCTC 10442. Phage libraries were prepared from S. aureus strain NCTC 10442 with partial Sau3A1 digests of chromosomal DNA of NCTC 10442 and lambda Dash II arms cleaved with BamHI (Stratagene) as described previously (14). Phages were propagated to produce plaques on E. coli XL1-Blue MRA(P2) and were lifted onto a nylon filter (Biodyne A; Pall BioSupport, East Hills, N.Y.). Plaque hybridization was performed with digoxigenin-labeled probes (Boehringer, Mannheim, Germany) as described previously (25). Chromosomal DNA fragments containing the left and right boundaries of SCCmec were cloned with the probes 11A and cR, respectively. The preparation of the two probes was described previously (14). With probe 11A, which corresponded to the chromosomal region flanking the left extremity of type II SCCmec or the chromosomal region upstream of attBscc of methicillin-susceptible strain NCTC 8325, lambda clone LO2 containing the left boundary of SCCmec was obtained. With probe cR, which corresponded to the chromosomal region downstream of attBscc of strain NCTC 8325, lambda clone LO21 containing the right boundary of SCCmec was obtained. With probe MA, which was prepared by PCR amplification with a set of primers (mA1 and mA2) based on the nucleotide sequence of the mecA gene (29), lambda clone LO5 containing ccr genes and the mecA gene was obtained.
Lambda clone LO7 containing the region upstream of the ccr genes was cloned by using an XbaI fragment 4.3 kb in size located at the left end of LO5 as a probe. The region downstream of mecA was sequenced with a long-range PCR-amplified DNA fragment 6.6 kb in size amplified by using mA3 and cR2 primers and chromosomal DNA as a template. Similarly, the region between the right end of LO2 and the left end of LO7 was identified by using a 7.5-kb DNA fragment amplified by long-range PCR with primers mE1 (based on the nucleotide sequence of LO2) and mE2 (based on the nucleotide sequence of LO7). The nucleotide sequences of the primers used in these experiments are listed in Table 3, except for the primers described in the previous reports (14, 17). The nucleotide sequence of the entire SCCmec of NCTC 10442 was determined by using the DNA fragments of lambda clones LO2, LO21, LO5, and LO7 and DNA fragments amplified by PCR.Amplification of DNA fragments by PCR and determination of the
entire nucleotide sequence of the SCCmec of 85/2082.
We have cloned the regions containing both boundaries of
SCCmec of MRSA 85/3907 (11) and determined
their nucleotide sequences (DDBJ/EMBL/GenBank accession no. AB047088
and AB047089). The regions containing both boundaries of the
SCCmec of 85/2082 were similar to those of 85/3907, and the
surrounding region of the mecA gene was similar to that of
MRSA strain ANS46 described previously by Dubin's group (4,
6). Taking advantage of this similarity, we could successfully
amplify DNA fragments covering the entire SCCmec of 85/2082
by long-range PCR with several sets of primers. The DNA fragment
corresponding to the chromosomal region upstream to the left extremity
of SCCmec was amplified by long-range PCR with a set of
primers, cLt1 and cLt4. The region spanning from the left extremity of
SCCmec to transposon 
Tn554 was amplified with
two sets of primers (cLt2 and mN2; mN1 and Tn554[171-146]). By using nine sets of primers, we could
amplify the region spanning from transposon Tn554 located
upstream of mecA to transposon Tn554 located
downstream of mecA. The sets of primers used were as
follows: mN3 and mN5 (the region in and around Tn554);
cad1 and mN6 plus mN4 and mN7 (the region from Tn554 to
downstream of mecA gene); mA3 and tetK1 (the region from
mecA to plasmid pT181); tetK4 and merA1 (the region from pT181 to the mercury operon); is-1 and merN plus merA2 and mN9 (the
mercury operon flanked by a pair of IS431 sites); mN8 and Tn554R; and mN11 and TnpA636 (the region spanning from
IS431 to transposase A of Tn554).
Tn554 (DDBJ/EMBL/GenBank accession no. L10909);
is-1, IS431mec (DDBJ/EMBL/GenBank accession no. X53818);
tetK1 and tetK4, plasmid pT181 (DDBJ/EMBL/GenBank accession no.
JO1764); and merA2 and merN, mer operon of pI258 (DDBJ/EMBL/GenBank
accession no. L29436).
The primers mN12 and mN13 were designed on the basis of the nucleotide
sequence of the right extremity of SCCmec of 85/3907 (DDBJ/EMBL/GenBank accession no. AB047089).
DNA manipulation. Colony hybridization and plaque hybridization were performed by using cellular DNA extracted from MRSA strains and digoxigenin-labeled probes (Boehringer Mannheim Biochemica, Mannheim, Germany) as described previously (31).
Large-scale and small-scale preparation of plasmid DNA, purification of phage plaques, extraction of DNA from purified phage particles, and subcloning of DNA fragments into plasmid vector pUC118 or pUC119 were performed by standard techniques (25). All of the enzymes for DNA manipulation were purchased from Takara Shuzo Co., Ltd., Kyoto, Japan, except for Taq DNA polymerase for PCR, which was purchased from Perkin-Elmer, Foster City, Calif. Nucleotide sequence determination was performed as described previously (10), with a Dye Terminator Cycle Sequencing FS Ready Reaction kit (Perkin-Elmer). A description of primers synthesized specifically for the primer extension sequence determination was omitted from the text.Isolation of SCCmec-excised strains. The method of obtaining SCCmec-excised strain N315ex from N315 has been described previously (17). The type I SCCmec-excised strain 85/1940ex was obtained by the method used for the preparation of N315ex, with a slight modification. Briefly, the recombinant plasmid, pSR, which carries ccrA and ccrB genes, was introduced into 85/1940 cells by electroporation. After overnight cultivation of the transformant strain 85/1940(pSR) on BHI agar containing tetracycline (10 µg/ml), cells were resuspended in saline and plated onto BHI agar containing tetracycline (10 µg/ml) for replica plating. The loss of methicillin resistance was examined first by replica plating on the agar with and without latamoxef (15 µg/ml). Latamoxef-susceptible colonies were selected and examined further to determine whether precise excision of type I SCCmec occurred by PCR with the primer set cR2 and cL1. Plasmid pSR was eliminated by serial cultivation in drug-free BHI broth at 43°C to obtain 85/1940ex.
The SCCmec-excised strain 85/2082ex was obtained by spontaneous excision of SCCmec from 85/2082. Cells were cultivated in BHI broth at 37°C for 2 to 3 days, and then a 0.1-ml portion of the cell suspension was inoculated into new BHI broth. After 38 days of serial passages, cells were plated onto BHI agar. The strains that had lost-lactam resistance were identified by replica plating onto BHI agar containing ceftizoxime (25 µg/ml), and precise excision of SCCmec of these strains was confirmed by PCR
with the primer set cLt3 and cR2 (Fig.
1).
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PCR amplification. PCR was performed essentially as described previously (31) with a 50-µl reaction volume and with thermal cycler Gene Amp 9600 (Perkin-Elmer Cetus Instruments, Emeryville, Calif.). Long-range PCR was performed with Expand Taq (Boehringer Mannheim Biochemica, Mannheim, Germany) according to the procedure recommended by the manufacturer. PCR products were purified with High Pure PCR product purification kit (Boehringer Mannheim Biochemica). The nucleotide sequences of the primers used in this experiment are described in Table 1 or were reported previously (14, 17).
Computer analysis of nucleotide and protein sequences. All of the analyses were carried out with programs in the Wisconsin Package (version 9.0; Genetics Computer Group, Madison, Wis.). A homology search was performed with the BLAST and TFastA programs for the EMBL (release no. 55.0) and GenBank (release no. 107.0) databases, and the FastA program for the SWISS-PROT database (release no. 35.0). Tree View software was obtained from the web site http://taxonomy.zoology.gla.ac.uk/rod/treview.html.
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RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Two mecA-carrying elements are new members of the SCCmec family. Initially, we tested whether the previously identified SCCmec on the chromosome of Japanese S. aureus strain N315 was also distributed in MRSA strains around the world. Thirty-eight representative epidemic strains listed in Table 1 were analyzed by dot-blot hybridization with 10 probes prepared in the N315 SCCmec. (See Fig. 1 for the location of the probes). A typical positive hybridization pattern was observed with the DNAs extracted from 9 of the 38 MRSA strains, but with others, only a few probes reacted positively, or the hybridization signal intensities were weak even if they reacted positively (Table 1). Since all of the listed strains possessed the mecA gene, the observation indicated that there were other types of genetic elements carrying the mecA gene on their chromosome.
From the strains with an atypical hybridization pattern to N315 SCCmec probes, two strains, NCTC 10442 and 85/2082, which represented two different (incomplete) hybridization patterns to N315 SCCmec probes, were chosen for cloning of the DNA region surrounding the mecA gene. With a strategy of cloning described in Materials and Methods, we identified from these strains new genetic elements that were inserted at the attB site of SCCmec (14). The boundaries of the element of NCTC 10442 were identified by comparing its nucleotide sequence with that of mecA-negative S. aureus type strain NCTC 8325 (Fig. 2). The boundaries of the element of 85/2082 were determined by comparing its nucleotide sequence with that of strain 85/2082ex, a spontaneous SCCmec-excised strain (Fig. 2). (We have previously reported that some MRSA strains spontaneously generate SCCmec excisant strains when cultivated in drug-free medium [14, 17]. Strain 85/2082 was one of the strains generating spontaneous excisants.)
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mecR1-mecA-IS431
[class B mec complex]), were created with the entire
SCCmec. Another common structure was a ccr
complex (composed of ccrA, ccrB homologue genes,
and surrounding ORFs) (Table 2 and Fig. 1). The ccrA and
ccrB genes encoding putative site-specific recombinases of
SCCmec are known to be responsible for the movement
(excision and integration) of N315 SCCmec from and into the
S. aureus chromosome (17). The corresponding ORFs found in the two other elements had a substantial homology to the
ccr genes of N315, although the ccrB gene of NCTC
10442 had a frameshift mutation (Table 2). Based on the structural similarities described above, these elements were considered to be new
members of the SCCmec family. Accordingly, the two elements found in NCTC 10442 and 85/2082 were designated type I and type III
SCCmec, respectively, and that of N315 was designated type II SCCmec. The ccr gene homologues found in each
SCCmec were designated ccrA and ccrB
genes with an Arabic numeral suffix to show the type of
SCCmec with which they were associated. It was noted that the ORFs adjacent to each type of ccr gene were also
conserved (amino acid identities of the corresponding ORFs were equal
to or greater than 47%) among the three types of SCCmec;
thus, they were unified as a ccr complex together with the
ccr genes.
Another region, called R-I, 3.5 kb in size was identified in type I
SCCmec that had a substantial similarity to the intervening region between Tn554 (or Tn554) and
mecI of type II and type III SCCmec (indicated by
large asterisks in Fig. 1). Two ORFs of unknown function were contained
in the R-I and corresponding regions of type II and type III
SCCmec, the amino acid identities of the deduced
polypeptides of which were greater than 52% (Table 2).
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Structure outside the integration site of SCCmec. Nucleotide sequencing of the regions around the left and right chromosome-SCCmec junctions revealed that the orfX genes of three MRSA strains, NCTC 10442, N315, and 85/2082, were extremely well conserved. All of the orfX genes were composed of 480 nucleotides with greater than 99% identity, and their encoded polypeptides were identical (Table 2). Thus, the nucleotide sequences of the chromosomal regions abutting the right junction point of SCCmec were extremely well conserved. In contrast, the nucleotide sequences abutting the left boundary of type III SCCmec differed substantially from those abutting type I and type II SCCmec.
Other genetic components of SCCmec. The size of type I SCCmec (NCTC10442) was 34,364 bp, and that of type III SCCmec (85/2082) was 66,896 bp. In contrast, the size of type II SCCmec (N315) was 53,017 bp. These differences in size were due to the presence of a type-specific DNA region in addition to the essential structures of SCCmec. The regions commonly shared by type I and type II SCCmec are shown in magenta; they were located at the right extremities of the elements between the rightmost IS431 copy and the right junction point (Fig. 1). Two ORFs of unknown function were contained in the region, and they were identical between the two types of SCCmec (Fig. 1). The nucleotide sequence of the region was also extremely well conserved between the two types (only 1 base substitution in 2, 120 bases), but type II SCCmec possessed an additional 102 bases of unique sequence in the very end of SCCmec (shown in red in Fig. 1).
The regions common to type II and type III SCCmec are shown in yellow; these regions were located between the ccr and mec complexes (Fig. 1). In the case of type III SCCmec, another copy of Tn554 was found downstream (to the right) of the mec complex, which was also associated with a ccr-complex-like structure (designated theccr complex in Fig. 1), just as Tn554 in the
mid-part of the element was associated with ccr complex. The
ccr complex was composed of a ccrB homologue
and three adjacent ORFs whose deduced amino acid sequences had greater
than 30% identity to the corresponding ORFs in the type II
ccr complex (Fig. 1 and Table 2).
The regions unique to each type of SCCmec are illustrated in
Fig. 1 in either blue (type I), red (type II), or green (type III). No
antibiotic resistance gene except for mecA was found in type
I SCCmec. In contrast, type III SCCmec contained
multiple antibiotic resistance genes. They were transposon
Tn554 encoding cadmium resistance inserted between
ccr and mec complexes, an integrated copy of
plasmid pT181 encoding tetracycline and mercury resistance, and another
transposon, Tn554, encoding erythromycin and spectinomycin
resistance. The latter three were found downstream (to the right) of
the mec complex, and pT181 and the mer operon were found bracketed by a pair of IS431 copies.
The ORFs contained in the left half of type I SCCmec were
type specific (shown in blue in Fig. 1), but mostly unknown with regard
to their function, except for one. The CE010 ORF potentially encoded a
polypeptide belonging to the Shine-Dalgarno repeat multigene family
(16), which was nearly identical to a large surface
protein of S. aureus designated plasmin-sensitive surface
protein (Pls) (8, 26). It was a repeat-rich protein
characteristically having unusual dipeptide repeats composed of serine
and aspartate residues. Another unique ORF of type III
SCCmec was Z059, the deduced amino acid sequence of which
showed a high similarity to HsdR of Klebsiella pneumoniae
and Salmonella enterica, which was flanked by
IS431 (Fig. 1). HsdR is a catalytic subunit of the
restriction-modification system (19). However, the
N-terminal portion of the ORF Z059 appeared to be deleted by
approximately 300 amino acid residues compared to the intact HsdR.
Distribution of the three types of SCCmec in clinical MRSA strains around the world. The 38 MRSA strains listed in Table 1 were reanalyzed with dot-blot hybridization with the probe sets prepared in each of the three types of SCCmec (see Fig. 1 for the locations of probes). Now, 34 strains showed typical hybridization patterns to either one of the three sets of probes (Table 1). In the 34 strains, additional PCR typing experiments of various genes and right extremity polymorphism (REP; see below) listed in Table 1 agreed with the dot-blot hybridization results. For example, all of the strains with type I SCCmec reacted positively to PCR detection of IS1272 and negatively to PCR detection of the mecI gene (Table 1). The results of ccr complex typing also agreed with the SCCmec typing results (Table 1).
We also used the PCR typing method designated mec right extremity polymorphism (MREP) typing (11). MREP typing is a quick SCCmec typing method that takes advantage of the polymorphism among the three types of SCCmec in the right extremity: type III had a unique nucleotide sequence, and type II SCCmec had additional 102-bp nucleotides to the right terminus of type I SCCmec (Fig. 1). PCR primers were prepared to bracket the right SCCmec-chromosome junction point to detect the polymorphism of the three types of SCCmec. MREP typing results of the 34 strains also agreed with those of SCCmec typing, but with two exceptions: strain 85/5328 did not react positively to any set of primers, and strain 93/H44, having type III SCCmec by dot-blot hybridization, was judged as having type I MREP (typically associated with type I SCCmec of NCTC 10442) (Table 1). Four strains, 81/108, 85/4547, 86/4372, and 87/25, did not hybridize typically to any of the three sets of SCCmec probes. However, strain 87/25 hybridized with all of the probes of type II SCCmec, except for probe 5. The other three strains appeared to carry the class B mec complex (IS1272-mecR1-mecA-IS431) characteristically found in type I SCCmec. However, strains
81/108 and 85/4547 responded to the primer set of the type II
ccr complex. In the case of strain 86/4372, a PCR using the
three sets of ccr primers did not amplify any DNA fragment
(see Discussion).
Experimental precise excision of type I SCCmec with
type 2 ccr genes.
Spontaneous precise excision of type
II SCCmec in the culture of MRSA strains can be detected by
the PCR amplification method by using the extracted DNA from the strain
as a template and by using a primer set of cR2 and cL1 bracketing the
integration site for SCCmec (designated attB PCR)
(see Fig. 1 for the location of primers, and see Table
3 for their sequences) (14,
17). In this study, a set of primers, cR2 and cLt3 (see Fig. 1
for the location of primers), was prepared to detect spontaneous
excision of type III SCCmec. DNA extracted from an overnight
culture of strain 85/2082 was positive with the set of primers, which
coincided with the fact that the spontaneously excised strain 85/2082ex was obtained after serial passages of the strain in drug-free medium.
In contrast, the set of primers cR2 and cL1, which theoretically detect
excision of type I as well as type II SCCmec, could not amplify DNA from the culture of NCTC 10442. This was in agreement with
the fact that ccrB1 of NCTC 10442 had a frameshift mutation (Table 2). Moreover, all nine strains with type I SCCmec
were negative with the attB PCR, and the mutation found in
the ccrB1 of NCTC 10442 was commonly found in all nine of
the ccrB1 genes. Therefore, we could not obtain a
spontaneous excisant strain from any of the strains having type I
SCCmec. To reconfirm the boundary of type I
SCCmec, therefore, we introduced type 2 ccr genes
into the type I SCCmec-carrying strain 85/1940. The strain
was used instead of NCTC 10442, because the latter strain was resistant to tetracycline; tetracycline resistance was used as a marker for
the selection of the transformants. The culture of a transformant strain 85/1940(pSR) generated -lactam-susceptible cells with a high
frequency. The nucleotide sequences around the attB region of the excisant strain 85/1940ex thus obtained are shown in Fig. 2. The
type I SCCmec integration site on the chromosome of
85/1940 coincided with that inferred by comparing the
corresponding regions of NCTC 10442 and NCTC 8325 strains
(Fig. 2).
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Molecular evolutionary relationship of members of the
ccr gene family and mecA genes.
Comparisons of the deduced amino acid sequences of ccrA and
ccrB genes of three types of SCCmec are shown in
Fig. 3. Since ccrB1 seemed to
be disrupted by a deletion of a single base, we have reconstituted a
potential ccrB1 gene (ccrB1*) by an addition of
adenine at the position where it seemed to be deleted and used its
deduced product for the comparison. All of the Ccr proteins were highly
basic, with pI values of 10.07 to 10.49, and shared the motifs of the
site-specific recombinases of the invertase-resolvase family in their
N-terminal domains (27). The catalytic serine residue of
the recombination active site was also conserved in all Ccr proteins.
Figure 4 illustrates the phylogenetic
relationship among the ccrA and ccrB genes of
three types of SCCmec. We also compared them with the
CcrB-like product of ORF CZ072 found in type III SCCmec and
with several site-specific recombinases of gram-positive bacteria as
well. The latter were the site-specific integrase of bacteriophage
TP901-1 of Lactococcus lactis; a site-specific recombinase
(5), spoIVCA, of Bacillus subtilis
(30); and a transposase, tnpX, of
Clostridium perfringens (3), which had
comparable sizes and substantial amino acid similarities to ccr genes. The phylogenetic tree showed that ccrA
and ccrB genes form separate subfamilies. The CZ072 ORF was
more closely related to the ccr genes of subfamily B than
those of subfamily A. The three site-specific recombinases of other
bacterial species were distantly related to either one of the two
ccr subfamilies (Fig. 4).
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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We have shown that there are at least three distinct types of SCCmec in the chromosome of MRSA worldwide. SCCmec was defined as the DNA element on the MRSA chromosome demarcated by a pair of direct repeats and inverted repeats, having ccr genes required for its movement and carrying the mecA gene (14, 17). As far as we could judge from the structure of the two elements newly identified in this study, they seem to constitute a family of SCCmec together with N315-type SCCmec.
The mecA gene is considered to have originated in some
coagulase-negative staphylococcus species (36) and was
then transferred into S. aureus to generate MRSA (1,
13, 32). It is likely that SCCmec serves as the
carrier of the mecA gene moving across staphylococcal
species, since mecA genes in other staphylococcal species
have never been found without the accompaniment of
SCCmec-like structure (T. Ito and Y. Katayama, unpublished
observation). Since both ccrA and ccrB genes are
required for the integration event, we considered that the
ccrB1 gene must have been intact when SCCmec was
introduced into the recipient S. aureus cell to produce NCTC 10442 or its precedent strain (17). However, so far, our
search for the intact ccrB1 in MRSA as well as in
methicillin-resistant coagulase-negative staphylococcus (MRC-NS)
strains isolated in Japan in 1980s and 1990s have not been successful
(K. Tsutsumimoto, unpublished observation). Successful excision of type
I SCCmec by type II ccr genes raised another
related question of whether the type 1 and type 2 ccr genes
were present as distinct types before or even soon after the
integration of SCCmec into the S. aureus
chromosome. We cannot rule out the possibility that the type 1 ccr genes were derived from type 2 ccr genes
after establishment of type II SCCmec in the MRSA chromosome
as a result of sequential accumulation of mutations. To finally clarify
the question, it would be necessary to find intact type 1 ccr genes retaining recombination function or,
alternatively, to test the functional integrity of ccrA1 in
combination with the ccrB1 gene artificially reconstructed from ccrB1 by eliminating the frameshift mutation. Study
in this direction is under way.
It is also noteworthy that type III SCCmec contained another
unit of ccr complex (ccr complex). Moreover,
the 15-bp direct repeat sequence present at the right end of
SCCmec was also found between the two IS431
copies in type III SCCmec, as illustrated in Fig. 1. These
findings indicate that the type III SCCmec is composed of
two separate SCCmec or SCC (cassette chromosome without mec complex) elements that were sequentially integrated in
the chromosome of 85/2082. We have observed that an experimental SCC plasmid carrying type 2 ccr genes, attSCC, and
tetL as a selective marker can integrate into N315
chromosome side-by-side with the type II SCCmec (H. Yuzawa,
unpublished data). In light of this, the putative right-part element of
type III SCCmec may be an SCC carrying a transposon,
Tn554, the erythromycin and spectinomycin resistance of
which serves as a selective marker. Alternatively, it may be another
copy of SCCmec in which the mec complex had been
deleted together with the ccrA gene after integration into the chromosome.
In contrast to the old strain, NCTC 10442, recent MRSA isolates are
resistant to many antibiotics besides -lactam antibiotics (9). Such a multiple resistance of MRSA is attained by the activity of IS431 copies downstream of mec
complex (Fig. 1). IS431 is known to serve as a chromosomal
deposit site for multiple resistance genes (21). The
integrated copies of pUB110 (in type II SCCmec) and pT181
(in type III SCCmec) were flanked by two copies of
IS431 (6, 22). Direct repeats were present at
both ends of these integrated plasmids. This suggests that these
plasmids were accumulated by homologous recombination events across two
copies of IS431: one present on the chromosome and the other
present on the plasmid (28).
We referred to the nucleotide sequences of two other MRSA strains by using the BLAST search program of The Institute for Genomic Research (TIGR) (http://www.tigr.org /cgi-bin/BlastSearch/blast.cgi?organism=s_aureus) and the Sanger Centre (http://www.sanger.ac.uk/Projects/S_aureus/). When we compared the nucleotide sequence of type I SCCmec, we found that strain COL, which is being sequenced by the genome project of TIGR, carried a DNA region corresponding to the element. The overall nucleotide identity of the region corresponding to type I SCCmec was 98% over 34,364 bases of alignment. The minor difference was found in the CE010 ORF potentially encoding pls, a polypeptide belonging to the SD repeat multigene family. On the other hand, strain 252 (EMRSA-16), which is being sequenced by the Sanger Centre, carried DNA regions divided into three contigs, which corresponded to type II SCCmec. There was a greater than 95% nucleotide identity between the two elements.
Thirty-four of 38 MRSA strains carried one of the three types of SCCmec. However, four strains reacted atypically to any of the three sets of probes. One of them, 85/25, may be interpreted simply as a carrier of type II SCCmec with a minor deletion in it: the chromosomal DNA of the strain hybridized with 9 of 10 type II probes positively and served as a positive template for the PCR detecting type 2 ccr genes (Table 1). The other three strains, however, were much more complex. The results of a PCR experiment suggested that they carried type II ccr complex (except for 85/4372), and the structure of the type ii right extremity (MREP type corresponding to type II SCCmec). However, the strains possessed the class B mec complex typically carried by type I SCCmec. There are several possible explanations for these cases. (i) The class B mec complex was introduced into a type II SCC (presumptive primordial element without a mec complex) located in a staphylococcus chromosome. (ii) Two SCC (or SCCmec) elements of type I and type II were cointegrated in the strains at the attB site, and, subsequently, homologous recombination between the two elements took place, leaving a chimeric SCCmec. In either case, the negative hybridization reaction of these strains with most probes of type I or type II SCCmec should be explained by the deletion of the region upstream of the ccr complex subsequent to their integration in the chromosome. If this was not the case, and there were unique DNA regions not hybridizable with either set of SCCmec probes, the elements carried by the strains may be referred to as other types of SCCmec.
With regard to strain 85/4372, no DNA fragment was amplified by PCR with a set of primers used for the ccr typing or those detecting the common nucleotide sequences of the three types of ccrA and ccrB genes (T. Ito, unpublished observation). Therefore, the ccr genes of this strain might have either been deleted or composed of a different nucleotide sequence from those of the three ccr genes described in this paper. Further experiments are required to clarify the complex structure of SCCmec of these strains.
There is no reason to limit the putative SCC to being only the conveyer of methicillin resistance alone. It might be serving as a vehicle for exchange of useful genes for the better survival of staphylococci in various environments. For example, plasmin-sensitive surface protein is found in type I SCCmec, and the Kdp operon, encoding potassium-dependent ATPase and its regulators, is carried by type II SCCmec. They, although mostly found as pseudogenes, might have been useful for the host cells to survive in their particular environment. Our proposal that SCC is a general genetic information exchange system of staphylococci and is not confined to antibiotic resistance also comes from our finding with an MSSA strain, ATCC 25923. The S. aureus type strain, isolated in 1945, long before the first isolation of MRSA (in 1961), carried a DNA fragment 5,877 bp in size (designated IE25923) inserted at exactly the same nucleotide position in orfX as that utilized by three SCCmecs for their integration. (The entire sequence of IE25923 is available under DDBJ/EMBL/GenBank accession no. AB047239.) Moreover, it had similar structural characteristics of SCCmecs at both ends, i.e., incomplete inverted repeats and direct repeats of 15 bp (Fig. 2). The nucleotides of both the left and right extremities showed high similarity to those of type III SCCmec: 92.6% (25 identical bases in 27 nucleotides at the left extremity) and 93.1% (27 identical bases in 29 nucleotides at the right extremity) (Fig. 2). However, the other region of IE25923 did not show any significant similarity to three types of SCCmec. No drug resistance gene was found in it. Unfortunately, no ORFs with inferable function based on the search of extant gene products or ccr genes were found in it. Therefore, IE25923 seems to be a remnant of SCC or SCCmec that was integrated in its complete form and then afterwards deleted with ccr as well as with mec complexes. Substantiation of our proposal will await finding a complete form of SCC carrying ccr genes, but with no mec complex on it.
In conclusion, we have found that the mec complex, conferring methicillin resistance to S. aureus, was conveyed by a novel family of the mobile genetic element SCCmec. SCCmec is defined by its characteristic structures at the extremities and by carriage of ccr as well as mec complexes. At least three distinct members make up the family. SCCmec may have evolved from a primordial mobile element, SCC, into which the mec complex was inserted. Exploration of staphylococcal genomes of more strains will find more diversified members of SCCmec as well as presumptive SCC, which will enable us to understand how staphylococcal species are exchanging genetic information to cope with antibiotics as well as the physiological selective pressure of the environment.
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ACKNOWLEDGMENTS |
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We thank B. Berger-Bachi for the kind gift of NCTC 8325 and J. Takahashi for excellent technical assistance.
This work was supported by the Core University Program under Japan Society for the Promotion of Science (JSPS), coordinated by the University of Tokyo, Graduate School of Medicine and Universiti Sains Malaysia, School of Medical Sciences; by grant 11670272 and the Specially Designated Research Promotion from the Japanese Ministry of Education; and by Grant for International Health Cooperation Research 11C-4 from the Japanese Ministry of Health and Welfare.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Bacteriology, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Phone: 81-3-5802-1040. Fax: 81-3-5684-7830. E-mail: hiram{at}med.juntendo.ac.jp.
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REFERENCES |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Antimicrobial Agents and Chemotherapy, May 2001, p. 1323-1336, Vol. 45, No. 5
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.5.1323-1336.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Noto, M. J., Fox, P. M., Archer, G. L.
(2008). Spontaneous Deletion of the Methicillin Resistance Determinant, mecA, Partially Compensates for the Fitness Cost Associated with High-Level Vancomycin Resistance in Staphylococcus aureus. Antimicrob. Agents Chemother.
52: 1221-1229
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Camargo, I. L. B. C., Gilmore, M. S.
(2008). Staphylococcus aureus--Probing for Host Weakness?. J. Bacteriol.
190: 2253-2256
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Noto, M. J., Kreiswirth, B. N., Monk, A. B., Archer, G. L.
(2008). Gene Acquisition at the Insertion Site for SCCmec, the Genomic Island Conferring Methicillin Resistance in Staphylococcus aureus. J. Bacteriol.
190: 1276-1283
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Moise, P. A., Smyth, D. S., El-Fawal, N., Robinson, D. A., Holden, P. N., Forrest, A., Sakoulas, G.
(2008). Microbiological effects of prior vancomycin use in patients with methicillin-resistant Staphylococcus aureus bacteraemia. J Antimicrob Chemother
61: 85-90
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Miragaia, M., Carrico, J. A., Thomas, J. C., Couto, I., Enright, M. C., de Lencastre, H.
(2008). Comparison of Molecular Typing Methods for Characterization of Staphylococcus epidermidis: Proposal for Clone Definition. J. Clin. Microbiol.
46: 118-129
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Donnio, P.-Y., Fevrier, F., Bifani, P., Dehem, M., Kervegant, C., Wilhelm, N., Gautier-Lerestif, A.-L., Lafforgue, N., Cormier, M., the MR-MSSA Study Group of the College de Bacterio, , Le Coustumier, A.
(2007). Molecular and Epidemiological Evidence for Spread of Multiresistant Methicillin-Susceptible Staphylococcus aureus Strains in Hospitals. Antimicrob. Agents Chemother.
51: 4342-4350
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Mombach Pinheiro Machado, A. B., Reiter, K. C., Paiva, R. M., Barth, A. L.
(2007). Distribution of staphylococcal cassette chromosome mec (SCCmec) types I, II, III and IV in coagulase-negative staphylococci from patients attending a tertiary hospital in southern Brazil. J Med Microbiol
56: 1328-1333
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Milheirico, C., Oliveira, D. C., de Lencastre, H.
(2007). Update to the Multiplex PCR Strategy for Assignment of mec Element Types in Staphylococcus aureus. Antimicrob. Agents Chemother.
51: 3374-3377
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Stephens, A. J., Huygens, F., Giffard, P. M.
(2007). Systematic Derivation of Marker Sets for Staphylococcal Cassette Chromosome mec Typing. Antimicrob. Agents Chemother.
51: 2954-2964
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Brady, J. M., Stemper, M. E., Weigel, A., Chyou, P.-H., Reed, K. D., Shukla, S. K.
(2007). Sporadic "Transitional" Community-Associated Methicillin-Resistant Staphylococcus aureus Strains from Health Care Facilities in the United States. J. Clin. Microbiol.
45: 2654-2661
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Milheirico, C., Oliveira, D. C., de Lencastre, H.
(2007). Multiplex PCR strategy for subtyping the staphylococcal cassette chromosome mec type IV in methicillin-resistant Staphylococcus aureus: 'SCCmec IV multiplex'. J Antimicrob Chemother
60: 42-48
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Goldstein, F., Perutka, J., Cuirolo, A., Plata, K., Faccone, D., Morris, J., Sournia, A., Kitzis, M. D., Ly, A., Archer, G., Rosato, A. E.
(2007). Identification and Phenotypic Characterization of a {beta}-Lactam-Dependent, Methicillin-Resistant Staphylococcus aureus Strain. Antimicrob. Agents Chemother.
51: 2514-2522
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Cookson, B. D., Robinson, D. A., Monk, A. B., Murchan, S., Deplano, A., de Ryck, R., Struelens, M. J., Scheel, C., Fussing, V., Salmenlinna, S., Vuopio-Varkila, J., Cuny, C., Witte, W., Tassios, P. T., Legakis, N. J., van Leeuwen, W., van Belkum, A., Vindel, A., Garaizar, J., Haeggman, S., Olsson-Liljequist, B., Ransjo, U., Muller-Premru, M., Hryniewicz, W., Rossney, A., O'Connell, B., Short, B. D., Thomas, J., O'Hanlon, S., Enright, M. C.
(2007). Evaluation of Molecular Typing Methods in Characterizing a European Collection of Epidemic Methicillin-Resistant Staphylococcus aureus Strains: the HARMONY Collection. J. Clin. Microbiol.
45: 1830-1837
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Hanssen, A.-M., Sollid, J. U. E.
(2007). Multiple Staphylococcal Cassette Chromosomes and Allelic Variants of Cassette Chromosome Recombinases in Staphylococcus aureus and Coagulase-Negative Staphylococci from Norway. Antimicrob. Agents Chemother.
51: 1671-1677
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O'Neill, E., Pozzi, C., Houston, P., Smyth, D., Humphreys, H., Robinson, D. A., O'Gara, J. P.
(2007). Association between Methicillin Susceptibility and Biofilm Regulation in Staphylococcus aureus Isolates from Device-Related Infections. J. Clin. Microbiol.
45: 1379-1388
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Sasaki, T., Kikuchi, K., Tanaka, Y., Takahashi, N., Kamata, S., Hiramatsu, K.
(2007). Methicillin-Resistant Staphylococcus pseudintermedius in a Veterinary Teaching Hospital. J. Clin. Microbiol.
45: 1118-1125
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de San, N., Denis, O., Gasasira, M.-F., De Mendonca, R., Nonhoff, C., Struelens, M. J.
(2007). Controlled Evaluation of the IDI-MRSA Assay for Detection of Colonization by Methicillin-Resistant Staphylococcus aureus in Diverse Mucocutaneous Specimens. J. Clin. Microbiol.
45: 1098-1101
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Miragaia, M., Thomas, J. C., Couto, I., Enright, M. C., de Lencastre, H.
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Kondo, Y., Ito, T., Ma, X. X., Watanabe, S., Kreiswirth, B. N., Etienne, J., Hiramatsu, K.
(2007). Combination of Multiplex PCRs for Staphylococcal Cassette Chromosome mec Type Assignment: Rapid Identification System for mec, ccr, and Major Differences in Junkyard Regions. Antimicrob. Agents Chemother.
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Heusser, R., Ender, M., Berger-Bachi, B., McCallum, N.
(2007). Mosaic Staphylococcal Cassette Chromosome mec Containing Two Recombinase Loci and a New mec Complex, B2. Antimicrob. Agents Chemother.
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French, G. L.
(2006). Bactericidal agents in the treatment of MRSA infections--the potential role of daptomycin. J Antimicrob Chemother
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Ma, X. X., Ito, T., Chongtrakool, P., Hiramatsu, K.
(2006). Predominance of Clones Carrying Panton-Valentine Leukocidin Genes among Methicillin-Resistant Staphylococcus aureus Strains Isolated in Japanese Hospitals from 1979 to 1985. J. Clin. Microbiol.
44: 4515-4527
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Nadarajah, J., Lee, M. J. S., Louie, L., Jacob, L., Simor, A. E., Louie, M., McGavin, M. J.
(2006). Identification of different clonal complexes and diverse amino acid substitutions in penicillin-binding protein 2 (PBP2) associated with borderline oxacillin resistance in Canadian Staphylococcus aureus isolates.. J Med Microbiol
55: 1675-1683
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Rogasch, K., Ruhmling, V., Pane-Farre, J., Hoper, D., Weinberg, C., Fuchs, S., Schmudde, M., Broker, B. M., Wolz, C., Hecker, M., Engelmann, S.
(2006). Influence of the Two-Component System SaeRS on Global Gene Expression in Two Different Staphylococcus aureus Strains.. J. Bacteriol.
188: 7742-7758
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Oliveira, D. C., Milheirico, C., de Lencastre, H.
(2006). Redefining a Structural Variant of Staphylococcal Cassette Chromosome mec, SCCmec Type VI.. Antimicrob. Agents Chemother.
50: 3457-3459
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Noto, M. J., Archer, G. L.
(2006). A Subset of Staphylococcus aureus Strains Harboring Staphylococcal Cassette Chromosome mec (SCCmec) Type IV Is Deficient in CcrAB-Mediated SCCmec Excision.. Antimicrob. Agents Chemother.
50: 2782-2788
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Guinane, C. M., Cotter, P. D., Ross, R. P., Hill, C.
(2006). Contribution of Penicillin-Binding Protein Homologs to Antibiotic Resistance, Cell Morphology, and Virulence of Listeria monocytogenes EGDe.. Antimicrob. Agents Chemother.
50: 2824-2828
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Waldron, D. E., Lindsay, J. A.
(2006). Sau1: a Novel Lineage-Specific Type I Restriction-Modification System That Blocks Horizontal Gene Transfer into Staphylococcus aureus and between S. aureus Isolates of Different Lineages.. J. Bacteriol.
188: 5578-5585
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Malik, S., Coombs, G. W., O'Brien, F. G., Peng, H., Barton, M. D.
(2006). Molecular typing of methicillin-resistant staphylococci isolated from cats and dogs. J Antimicrob Chemother
58: 428-431
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Oliveira, D. C., Milheirico, C., Vinga, S., de Lencastre, H.
(2006). Assessment of allelic variation in the ccrAB locus in methicillin-resistant Staphylococcus aureus clones. J Antimicrob Chemother
58: 23-30
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Jansen, W. T. M., Beitsma, M. M., Koeman, C. J., van Wamel, W. J. B., Verhoef, J., Fluit, A. C.
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50: 2072-2078
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Sobral, R. G., Ludovice, A. M., de Lencastre, H., Tomasz, A.
(2006). Role of murF in Cell Wall Biosynthesis: Isolation and Characterization of a murF Conditional Mutant of Staphylococcus aureus.. J. Bacteriol.
188: 2543-2553
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Desjardins, M., Guibord, C., Lalonde, B., Toye, B., Ramotar, K.
(2006). Evaluation of the IDI-MRSA Assay for Detection of Methicillin-Resistant Staphylococcus aureus from Nasal and Rectal Specimens Pooled in a Selective Broth. J. Clin. Microbiol.
44: 1219-1223
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Chongtrakool, P., Ito, T., Ma, X. X., Kondo, Y., Trakulsomboon, S., Tiensasitorn, C., Jamklang, M., Chavalit, T., Song, J.-H., Hiramatsu, K.
(2006). Staphylococcal Cassette Chromosome mec (SCCmec) Typing of Methicillin-Resistant Staphylococcus aureus Strains Isolated in 11 Asian Countries: a Proposal for a New Nomenclature for SCCmec Elements. Antimicrob. Agents Chemother.
50: 1001-1012
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Tenover, F. C., McDougal, L. K., Goering, R. V., Killgore, G., Projan, S. J., Patel, J. B., Dunman, P. M.
(2006). Characterization of a Strain of Community-Associated Methicillin-Resistant Staphylococcus aureus Widely Disseminated in the United States. J. Clin. Microbiol.
44: 108-118
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Yang, J. A., Park, D. W., Sohn, J. W., Kim, M. J.
(2006). Novel PCR-Restriction Fragment Length Polymorphism Analysis for Rapid Typing of Staphylococcal Cassette Chromosome mec Elements. J. Clin. Microbiol.
44: 236-238
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Stephens, A. J., Huygens, F., Inman-Bamber, J., Price, E. P., Nimmo, G. R., Schooneveldt, J., Munckhof, W., Giffard, P. M.
(2006). Methicillin-resistant Staphylococcus aureus genotyping using a small set of polymorphisms. J Med Microbiol
55: 43-51
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van der Zee, A., Heck, M., Sterks, M., Harpal, A., Spalburg, E., Kazobagora, L., Wannet, W.
(2005). Recognition of SCCmec Types According to Typing Pattern Determined by Multienzyme Multiplex PCR-Amplified Fragment Length Polymorphism Analysis of Methicillin-Resistant Staphylococcus aureus. J. Clin. Microbiol.
43: 6042-6047
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Deurenberg, R. H., Vink, C., Oudhuis, G. J., Mooij, J. E., Driessen, C., Coppens, G., Craeghs, J., De Brauwer, E., Lemmen, S., Wagenvoort, H., Friedrich, A. W., Scheres, J., Stobberingh, E. E.
(2005). Different Clonal Complexes of Methicillin-Resistant Staphylococcus aureus Are Disseminated in the Euregio Meuse-Rhine Region. Antimicrob. Agents Chemother.
49: 4263-4271
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Zhang, K., McClure, J.-A., Elsayed, S., Louie, T., Conly, J. M.
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43: 5026-5033
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Qi, W., Ender, M., O'Brien, F., Imhof, A., Ruef, C., McCallum, N., Berger-Bachi, B.
(2005). Molecular Epidemiology of Methicillin-Resistant Staphylococcus aureus in Zurich, Switzerland (2003): Prevalence of Type IV SCCmec and a New SCCmec Element Associated with Isolates from Intravenous Drug Users. J. Clin. Microbiol.
43: 5164-5170
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Kwon, N. H., Park, K. T., Moon, J. S., Jung, W. K., Kim, S. H., Kim, J. M., Hong, S. K., Koo, H. C., Joo, Y. S., Park, Y. H.
(2005). Staphylococcal cassette chromosome mec (SCCmec) characterization and molecular analysis for methicillin-resistant Staphylococcus aureus and novel SCCmec subtype IVg isolated from bovine milk in Korea. J Antimicrob Chemother
56: 624-632
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Berglund, C., Molling, P., Sjoberg, L., Soderquist, B.
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43: 4448-4454
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Boyle-Vavra, S., Ereshefsky, B., Wang, C.-C., Daum, R. S.
(2005). Successful Multiresistant Community-Associated Methicillin-Resistant Staphylococcus aureus Lineage from Taipei, Taiwan, That Carries Either the Novel Staphylococcal Chromosome Cassette mec (SCCmec) Type VT or SCCmec Type IV. J. Clin. Microbiol.
43: 4719-4730
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Donnio, P.-Y., Oliveira, D. C., Faria, N. A., Wilhelm, N., Le Coustumier, A., de Lencastre, H.
(2005). Partial Excision of the Chromosomal Cassette Containing the Methicillin Resistance Determinant Results in Methicillin-Susceptible Staphylococcus aureus. J. Clin. Microbiol.
43: 4191-4193
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Arakere, G., Nadig, S., Swedberg, G., Macaden, R., Amarnath, S. K., Raghunath, D.
(2005). Genotyping of Methicillin-Resistant Staphylococcus aureus Strains from Two Hospitals in Bangalore, South India. J. Clin. Microbiol.
43: 3198-3202
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Hisata, K., Kuwahara-Arai, K., Yamanoto, M., Ito, T., Nakatomi, Y., Cui, L., Baba, T., Terasawa, M., Sotozono, C., Kinoshita, S., Yamashiro, Y., Hiramatsu, K.
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43: 3364-3372
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Said-Salim, B., Mathema, B., Braughton, K., Davis, S., Sinsimer, D., Eisner, W., Likhoshvay, Y., DeLeo, F. R., Kreiswirth, B. N.
(2005). Differential Distribution and Expression of Panton-Valentine Leucocidin among Community-Acquired Methicillin-Resistant Staphylococcus aureus Strains. J. Clin. Microbiol.
43: 3373-3379
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Trindade, P. d. A., Pacheco, R. L., Costa, S. F., Rossi, F., Barone, A. A., Mamizuka, E. M., Levin, A. S.
(2005). Prevalence of SCCmec Type IV in Nosocomial Bloodstream Isolates of Methicillin-Resistant Staphylococcus aureus. J. Clin. Microbiol.
43: 3435-3437
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O'Brien, F. G., Lim, T. T., Winnett, D. C., Coombs, G. W., Pearson, J. C., Delgado, A., Langevin, M. J., Cantore, S. A., Gonzalez, L., Gustafson, J. E.
(2005). Survey of Methicillin-Resistant Staphylococcus aureus Strains from Two Hospitals in El Paso, Texas. J. Clin. Microbiol.
43: 2969-2972
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Shore, A., Rossney, A. S., Keane, C. T., Enright, M. C., Coleman, D. C.
(2005). Seven Novel Variants of the Staphylococcal Chromosomal Cassette mec in Methicillin-Resistant Staphylococcus aureus Isolates from Ireland. Antimicrob. Agents Chemother.
49: 2070-2083
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Josefsson, E., Juuti, K., Bokarewa, M., Kuusela, P.
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Hanssen, A.-M., Fossum, A., Mikalsen, J., Halvorsen, D. S., Bukholm, G., Sollid, J. U. E.
(2005). Dissemination of Community-Acquired Methicillin-Resistant Staphylococcus aureus Clones in Northern Norway: Sequence Types 8 and 80 Predominate. J. Clin. Microbiol.
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Katayama, Y., Robinson, D. A., Enright, M. C., Chambers, H. F.
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Holmes, A., Ganner, M., McGuane, S., Pitt, T. L., Cookson, B. D., Kearns, A. M.
(2005). Staphylococcus aureus Isolates Carrying Panton-Valentine Leucocidin Genes in England and Wales: Frequency, Characterization, and Association with Clinical Disease. J. Clin. Microbiol.
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Weese, J. S.
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(2005). Community-Associated Methicillin-Resistant Staphylococcus aureus and Its Emerging Virulence. Clin Med Res
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Miller, L. G., Perdreau-Remington, F., Rieg, G., Mehdi, S., Perlroth, J., Bayer, A. S., Tang, A. W., Phung, T. O., Spellberg, B.
(2005). Necrotizing Fasciitis Caused by Community-Associated Methicillin-Resistant Staphylococcus aureus in Los Angeles. NEJM
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Gill, S. R., Fouts, D. E., Archer, G. L., Mongodin, E. F., DeBoy, R. T., Ravel, J., Paulsen, I. T., Kolonay, J. F., Brinkac, L., Beanan, M., Dodson, R. J., Daugherty, S. C., Madupu, R., Angiuoli, S. V., Durkin, A. S., Haft, D. H., Vamathevan, J., Khouri, H., Utterback, T., Lee, C., Dimitrov, G., Jiang, L., Qin, H., Weidman, J., Tran, K., Kang, K., Hance, I. R., Nelson, K. E., Fraser, C. M.
(2005). Insights on Evolution of Virulence and Resistance from the Complete Genome Analysis of an Early Methicillin-Resistant Staphylococcus aureus Strain and a Biofilm-Producing Methicillin-Resistant Staphylococcus epidermidis Strain. J. Bacteriol.
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Juuti, K., Ibrahem, S., Virolainen-Julkunen, A., Vuopio-Varkila, J., Kuusela, P.
(2005). The pls Gene Found in Methicillin-Resistant Staphylococcus aureus Strains Is Common in Clinical Isolates of Staphylococcus sciuri. J. Clin. Microbiol.
43: 1415-1419
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