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Secret of Success of Human Pathogen
Secret of Success of Human Pathogen
Secret of Success of Human Pathogen
isolates
electrophoresis (PFGE)we identified five major 100
MRSA clones that accounted for almost 70% of the over
3000 MRSA isolates recovered in hospitals mainly in 80
southern and eastern Europe, South America, and the 60
USA. Most of our surveillance studies were done in these
areas. Multilocus sequencing typing (MLST) of 40
representative isolates of this collection showed that 20
these five pandemic MRSA clones have evolved from
0
only two distinct ancestral genetic backgrounds, one of
which can be traced back to the very first European 1950 1960 1970 1980 1990
MRSA isolates and also to meticillin susceptible S aureus Year of isolation
strains circulating in Danish hospitals during the mid to Figure 1. Sequential appearance of meticillin-susceptible and meticillin-
late 1950sie, shortly before the introduction of resistant blood isolates of S aureus belonging to phage group III and the
related 83A complex in Denmark. The numbers plotted represent all S
meticillin into therapy. The second lineage with a
aureus blood isolates identified in Denmark during the particular period
completely different MLST profile included MRSA (adapted from reference 33).
frequently recovered in the USA, Japan, and among
paediatric isolates from several parts of the world. A few
isolates with a third distinct MLST type corresponding infections, bacteraemia, infections of the central nervous
to that of EMRSA-16 were also detected in the early system, respiratory and urinary tracts, and infections
Danish isolates. The four structural types of mec associated with intravascular devices and foreign bodies.1,2
element, the heterologous DNA segment containing the Most S aureus strains are opportunistic pathogens that can
meticillin resistance determinant mecA, were present in colonise individuals, without symptoms, for either short or
unique combinations with the MRSA clonal types. Our extended periods of time, causing disease when the immune
findings establish evolutionary associations in the most system becomes compromised. Indications are that this
widely spread pandemic clones of MRSA. The bacterial pathogen has affected human beings since
epidemiological factors that contributed to the massive prehistoric times. Before the antibiotic era S aureus diseases
dissemination of a few MRSA clones are not well had high mortality rates. In 1941 the mortality rate of S aureus
understood. We suggest, however, that the secrets of bacteraemia at the Boston City hospital was reported to be
effectiveness of MRSA could be hidden in the unique 82%.3 In versatility of pathogenic strategies, numbers of
genetic background of a surprisingly few lineages of S virulence factors, and capacity to survive and multiply in a
aureus particularly well able to cope with the wide range of environments, S aureus is unsurpassed by any
contemporary clinical environment. other human pathogen. The immense genetic repertoire of
Lancet Infectious Diseases 2002; 2: 18089 this bacterium for adapting to rapidly changing and
DCO and HdL are at the Instituto de Tecnologia Qumica e
The adaptive power of Staphylococcus aureus: Biolgica, Oeiras, Portugal; and all authors are at Rockefeller
emergence of antibiotic-resistant strains University, New York, USA
Staphylococcus aureus has long been recognised as one of the Correspondence: Dr Hermnia de Lencastre, Rockefeller University,
major human pathogens responsible for a wide range of 1230 York Avenue, New York, NY 10021, USA. Tel 212 327 8278;
afflictions from minor infections of the skin to wound fax 212 327 8688; email lencash@mail.rockefeller.edu
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Molecular evolution of MRSA
Review
uniformly hostile environments was repeatedly shown by the bacterial pathogens such as S aureus. Effective lineages of
emergence of S aureus strains that acquired resistance contemporary pathogens must excel in several capacities: they
mechanisms to virtually all antimicrobial agents shortly after must be able to acquire resistant genes and to construct
the introduction of these drugs into clinical practice. regulatory mechanisms that can adjust resistance levels to
The introduction of benzylpenicillin into chemotherapy increasing concentrations of the antimicrobial agent. In the
in the early 1940s found S aureus fully susceptible and several environment, the resistance-related determinants must find
of the first successes of penicillin therapy were related to the their way into genetic backgrounds that assure the capacity to
cure of formerly untreatable staphylococcal diseases.4 But by compete with other bacteria. Pathogens must be able to
the mid 1950s the number of S aureus clinical isolates showing spread, establish ecological reservoirs, colonise, and cause
high-level resistance to penicillin increased rapidly, to such an disease.
extent that penicillin ceased to be a useful therapeutic Detection and elucidation of the mechanisms of drug
agent against staphylococcal infections. The mechanism of resistance requires the collection of S aureus isolates from the
penicillin resistance involved the acquisition of a plasmid- clinical environment. Strain collection in increasingly
borne penicillinase capable of degrading the antibiotic before sophisticated epidemiological contexts and analysis of the
it had reached its cellular targets. The effects of this plasmid strains by molecular typing techniques has led to the
epidemic were first seen on hospital isolates of S aureus but emergence of the new discipline, molecular epidemiology,
soon afterwards the penicillinase-based mechanism found its which has greatly improved the capacity of hospitals to track
way into community isolates as well.5 Currently, most the source and transmission routes of bacterial pathogens
S aureus isolates that cause disease or simply colonise healthy during hospital outbreaks. Beyond producing sophisticated
individuals are resistant to penicillin. A study of the S aureus tools for epidemiological tracking, molecular epidemiology
colonising flora of 1001 healthy volunteers showed that 97% has become an alliance of clinical and molecular
of the S aureus isolates recovered carried the resistant trait to microbiologists that began to tackle issues of the population
penicillin.6 structure of microbial pathogens in their native
The power of S aureus to mount counter-strategies to environment.1217
additional products of the antibiotic era besides penicillin
is also well documented. Records of the Danish Health Board Evolutionary zero time in the emergence of MRSA
registered the years of introduction of various antimicrobials The emergence and dissemination of meticillin-resistant
into clinical practice, beginning with penicillin in 19451946, S aureus is a case of accelerated evolution in which these
streptomycin in 1948, tetracycline in 1950, and erythromycin bacteria are propelled by the selective pressure of vast
in 1953.5 The same records indicate that S aureus bloodstream quantities of antimicrobial-related agents in the planetary
isolates resistant to penicillin, streptomycin, tetracycline, and environment.18 The evolutionary zero time of this process is
erythromycin were recovered as early as 1957. The the acquisition of the central genetic determinant of MRSA,
introduction of meticillin in clinical practice in 1960 the mecA gene, a 21 kb stretch of DNA that is not native to
was followed by the appearance of the first bloodstream the species S aureus and which is embedded in a larger
isolate of S aureus that was resistant not only to penicillin, blockup to 60kbof additional foreign DNA called the
streptomycin, and tetracycline (and occasionally to mec element19 or staphylococcal chromosomal cassette
erythromycin), but to meticillin as well. (SCCmec),20 which together with the mecA is incorporated
Meticillin, originally called celbenine, was the first into the S aureus chromosome at a site-specific location.21,22
mechanism-based antimicrobial agent: it is a semisynthetic The mecA gene encodes for a 78 kDa penicillin-binding
derivative of penicillin chemically modified to withstand the protein (PBP2A), which has very low affinity for beta-lactam
degradative action of penicillinase.7 The drug was introduced antibiotics.2325 Recent evidence indicates that PBP2A is a
into therapy in Europe in 19591960. 1 year later, the first transpeptidase26 that, assisted by the transglycosidase domain
meticillin-resistant S aureus (MRSA) strains were detected,8
Table 1. Resolution of three molecular typing methods (adapted
and the first clinical failure by an MRSA strain was described,9
from reference 30)
followed by a report on the first MRSA outbreak in 1963.10
Since the 1960s, MRSA strains have spread among hospital Typing method(s)* Number of patterns
isolates in several waves, which eventually disseminated these mecA + Tn554 + PFGE subtype 97
strains worldwide. Recent surveillance studies in hospitals in mecA + Tn554 + PFGE 42
various parts of the world indicate a varying incidence of mecA + Tn554 23
MRSA strains depending on the country and the hospital. In mecA + PFGE subtype 86
the USA, the National Nosocomial Infections Surveillance mecA + PFGE 29
System (NNISS) recorded an increase of MRSA in large US mecA 9
hospitals, from 4% in the 1980s to 50% in the late 1990s. In
Tn554 +PFGE subtype 92
some hospitals resistance frequencies as high as 80% have
Tn554 +PFGE 34
been recorded.11
Tn554 9
PFGE subtype 80
Antibiotic resistance in an evolutionary context
The introduction of vast quantities of structurally diverse PFGE 20
antimicrobial agents into the human environment during the *ClaI-mecA vicinity polymorphisms (mecA); ClaI-Tn554 insertion patterns; PFGE major
past 60 years has presented a new set of challenges to patterns and subtypes.
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Review Molecular evolution of MRSA
Table 2. Properties of historically early strains of MSSA recovered in Denmark (adapted from reference 33)
Strain Date Origin* Phage group PFGE pattern Antibiogram spaA type MLST profile Genetic background
E213 1957 ND 83A A19 PST YHGFMBQBLO 3 3 1 1 4 4 16 A1
E298 1958 ND 83A A19 PST YHGFMBQBLO
E306 1958 ND 83A A19 PST YHGFMBQBLO 3 3 1 1 4 4 16 A1
E712 1959 1 83A A19 PST YO
E803 1959 2 83A A22 PST YHGFMBQBLO 3 3 1 1 4 4 16 A1
E1038 1960 3 83A A23 PST YHGFMBQBLO
E1045 1960 4 83A A19 PST YHGFMBQBLO
E1210 1961 5 83A A19 PST YHGFMBQBLO
E1215 1961 6 83A A24 PST YHGFMBQBLO 3 3 1 1 4 4 16 A1
E1404 1962 7 83A A19 PST YHGFMBQBLO
E1600 1963 9 83A A19 PST YHGGFMBQBLO
E1611 1963 10 83A A25 PST YHGFMBQBLO
E1907 1964 11 83A A20 PST YHGFMBQBLO 3 3 1 1 4 4 16 A1
E2251 1965 14 83A A19 PST YHGFMBQBLO 3 3 1 1 4 4 16 A1
E2260 1965 15 83A A20 PST YHFGFMBQBLO 3 3 1 1 4 4 16 A1
E2310 1965 16 83A A26 PST YHGFMBQBLO
E2611 1966 18 83A A21 PST YHGFMBQBLO
E228 1957 ND 83A f PS YHGFMBQBLO 3311443 A3
E1410 1962 8 NT g PS WGKAKAOMQ 2222632 C
E2104 1964 4 III e1 P TJMBMDMGMK 1 4 1 4 12 1 10 B
E3001 1967 7 83A e2 P TJMBMDMMK 1 4 1 4 12 1 10 B
E3008 1967 19 III A27 P YHGFMBQBLO 3311443 A3
E2615 1966 17 III d P UJFKBPE
E3410 1968 20 83A d Susceptible UJFKBPE 1111111
E3445 1968 7 83A d Susceptible UJFKBPE
*Numbers represent different cities; P=penicillin, S=streptomycin, T=tetracycline. ND=not determined, NT=not typable.
of the native PBP2 of S aureus,27 takes over the function of cell of a group of MRSA recovered in a surveillance study in
wall biosynthesis in the presence of beta-lactam antibiotics in 12 hospitals in New York showed that the highest resolution
the medium. was achieved by the PFGE patterns.30 PFGE has
been recognised as a highly discriminatory technique
Molecular typing of MRSA and suggested to be the gold standard for outbreak
The purpose of this overview is not to detail the molecular investigations.31 Two sequencing-based techniques,
mechanism of meticillin resistance but to survey recent multilocus-sequencing type (MLST) and spaA typing, have
information that has allowed insights into the evolutionary been developed recently, with great potential for global
process that has led to the emergence of a relatively few epidemiology studies.13,15,32 MLST is based on the DNA
pandemic clones of MRSA. Critical for obtaining this sequencing of the internal fragments of seven unlinked
information were the combination of several molecular housekeeping genes (arcC, aroE, glpF, gmk, pta, tpi, and
typing techniques, the elucidation of the structure of the mec yqiL) and spaA typing is based on the DNA sequencing of
elements,22 and the availability of large collections of MRSA the polymorphic region of protein A, a superantigen of
in our laboratories. These collections, from various parts of S aureus.
the world, include the strain collection of the Danish
surveillance system that preserved every S aureus blood- The nature of early MRSA isolates
stream isolate recovered in Denmark since the mid 1950s.5 The preservation of all S aureus bacteraemic isolates in
A particularly successful strategy for MRSA typing Denmark since the mid 1950s has allowed us to look at the
has been the combination of three molecular techniques epidemiological context of the appearance of MRSA in that
with different discriminative characteristics:28 (i) country. Among 3704 S aureus bacteraemic isolates
macrorestriction pattern of chromosomal DNA after SmaI recovered between 1957 and 1970, 646 MRSA isolates were
digestion and separation of the fragments by pulsed-field gel identified and all but nine of these were resistant not only to
electrophoresis (PFGE); (ii) polymorphisms in the vicinity meticillin but to penicillin, streptomycin, tetracycline, and
of the mecA gene detected by probing ClaI-digested DNAs often to erythromycin. Furthermore, 616 of these 646
with a mecA probe;29 and (iii) transposon Tn554 insertion isolates (95%) belonged to unique phage groups called
patterns detected by probing ClaI-digested DNAs with a phage group III or the related 83A complex.5 Data from the
specific probe.29 The individual and combined resolving Danish surveillance system indicate that almost half of all
ability of these methods is shown in table 1, where analysis S aureus bacteraemic isolatesboth MRSA and meticillin-
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Molecular evolution of MRSA
Review
PA l n l l NY
Japan NJl l CT Scotland n
l n Denmark
l Taiwan
n l Poland
n Germany
Belgium n
Colombia l n l Czech Republic
l l
l France n
Brazil n Switzerland
l l Hungary
l l
l
Chile l l Uruguay n
l Portugal l n Spain n Italy
n Iberian clone lll l
l Brazilian/Hungarian clone l l Argentina
l Paediatric clone ll
l NY/Japan clone
susceptible S aureus (MSSA)recovered in Denmark evidence pointing in this direction was the sequential
during this period belonged to these phage groups. The appearance of MSSA strains belonging to phage group III
very first European MRSA isolates identified in the UK and/or 83A with the PST antibiotype, and the appearance of
also belonged to the same phage group and were resistant MRSA strains belonging to the same phage group and
to penicillin, streptomycin, tetracycline (PST), and sharing the same PST or PSTE multiresistance pattern in
occasionally to erythromycin (PSTE) as well.8,10 These addition to being meticillin resistantPSTM and PSTEM
observations strongly suggested that we might be able to (figure 1). Molecular typing with MLST, PFGE, and spaA
identify among these Danish MSSA isolates one of the first S typing fully confirmed this point.33 The overwhelming
aureus lineages that received the mecA gene. Additional majority of historically early MSSA and MRSA isolates from
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Review Molecular evolution of MRSA
Denmark and the earliest MRSA 89 990 991 992 993 994 995 996 997
isolates from the UK shared identical City Hospital 19 1 1 1 1 1 1 1 1
or very similar molecular profiles Porto ns V Castelo 1 s nl nl nl nl nl nl
nls 2 l l l
(table 2). Characterisation of these Lisbon
V N nl Guarda 3 nl
earliest, archaic, strains of MRSA Gaia nl 4 n n n
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Molecular evolution of MRSA
Review
mecA
SCCmec type IV Paediatric clone IS431
LJ RJ
mecR1 dcs orfX
ccrAB4 IS1272 HVR
Figure 5. SCCmec element structures and variants. The basic structures of SCCmec types I, II III and IV are depicted, as well as its variants SCCmec IA
21,22,38,39
and IIIA. LJ=chromosomal left junction, RJ= chromosomal right junction.
described in 1992 in Brazil and then in Portugal, Argentina, hospitals and at different time intervals in a country
Uruguay, Chile, and the Czech Republic. The Hungarian providing evidence for the stability of epidemic clones over
clone was extensively disseminated among hospitals in that time. Figure 3 shows the MRSA clonal distribution in
country and was most recently also identified in Taiwan. ten hospitals in six Portuguese cities during 9 years. Figure 4
The New York/Japan clone was identified as the dominant shows that in the largest Portuguese teaching hospital
MRSA in hospitals in metropolitan New York, New Jersey, located in Coimbra, during three distinct surveillance
Pennsylvania, and Connecticut, and also in one hospital in periods, the Iberian and Brazilian clones were present in
Tokyo, Japan. The paediatric clone was first reported in a different proportions but together accounted for virtually all
paediatric hospital in Portugal in 1992 and was also reported the MRSA isolates. In this case, molecular typing techniques
in Poland, USA, Argentina, and Colombia (for a list of were able to document the introduction of the Brazilian
references concerning the spread of the MSRA pandemic clone during the first surveillance period. During the
clones see table 1 of reference 37). following surveillance periods, the prevalence of this clone
Molecular typing techniques have not only allowed the increased from 5% to 38%, whereas the previous endemic
identification of pandemic clones of MRSA, but have also Iberian MRSA clone decreased from 89% to 55%.38
enabled us to monitor MRSA clones circulating in different
Identification of two distinct ancestral lineages
Table 4. Genetic backgrounds and SCCmec types of the pandemic among the five pandemic MRSA clones
MRSA clones. The primary criterion used for the initial classification of
Clonal spaA type MLST Profile Genetic SCCmec MRSA isolates into the five pandemic clonal types was their
Type motif Background type PFGE pattern. PFGE is a high-resolution technique capable
Archaic MBQBLO 3-3-1-1/12-4-4-16 A1 I of registering DNA rearrangements and acquisition or loss
Iberian MBQBLO 3-3-1-1/12-4-4-16 A2 IA of genetic determinantsie, genetic events that can happen
Clone V MBQBLO 3-3-1-1-4-4-3 A3 IV
on a short time scale. While providing a high degree
of resolution, this technique could blur long-range
Brazilian KAOMQ 2-3-1-1-4-4-3 A4 IIIA evolutionary associations in MRSA strains. By contrast,
Hungarian KAOMQ 2-3-1-1-4-4-3 A4 III MLST variations accumulate slower than variations in
NY/Japan DMGMK 1-4-1-4-12-1-10 B II
PFGE, since they arise from neutral mutations in
Pediatric DMGMK 1-4-1-4-12-1-10 B IV
housekeeping genes. Thus, the same MLST allelic profile
could include temporally distant strains that have
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Review Molecular evolution of MRSA
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Molecular evolution of MRSA
Review
(allelic profile 7-6-1-5-8-8-6, background D) and E-MRSA 16 S aureus seems to be predominantly due to the clonal
(allelic profile 2-2-2-2-3-3-2, background C), two MRSA expansion of very few lineages. A tentative scheme outlining
clones that currently represent the most frequent MRSA in steps in the evolution of MRSA clonal families and the
UK hospitals.40,41 E-MRSA 15 was also detected in Germany.42 acquisition of SCCmec elements is presented in figure 6. The
An E-MRSA 16 representative strain is being sequenced. proposed evolutionary associations are primarily based on
Examination of its preliminary genome sequence data the properties of MRSA strains analysed and, in our case,
indicates that it harbours a SCCmec type II, the same mec these came mainly from sources in southern and eastern
element shown to be resident in a completely different Europe, Latin America, and the USA. Important findings
genetic background: background B characteristic of the New were also made possible by the availability of the Danish
York/Japan clone. The presence of SCCmec type II in both of MRSA collection and by the information available in the
these distinct genetic backgrounds (B and C) could represent MLST database. Analysis of isolates from other geographic
either an independent acquisition event or horizontal transfer areas would be of great interest.
of the mec element from one S aureus strain to another.
MLST studies of MSSA strains uncovered a great diversity The origin of the mec element
of allelic profiles,12,13 which contrasts with the clonal structure The origin of the mec element is not known. The assembly of
of the highly epidemic MRSA. The worldwide spread of the several mec element structures may have involved
MRSA seems to be primarily driven by the dissemination of a multiple hosts, possibly among coagulase-negative
few pandemic clones in which the mec element found genetic staphylococci.44 A close homologue of the S aureus mecA gene
backgrounds that provided appropriate fitness for virulence was recently identified as a gene native to the animal
and epidemic spread of the bacteria. One of these genetic commensal species Staphylococcus sciuri, most strains of
backgroundsA1has recently been identified in MSSA which are fully susceptible to meticillin and all beta-lactam
strains that were highly prevalent in the late 1950s in antibiotics.45,46 The insertion sequence IS1272 present in
Denmark.33 MSSA with genetic backgrounds A3 (clone V), B SCCmec types I and IV appears in several copies in the
(Brazilian and Hungarian clones), and C (E-MRSA 16) were Staphylococcus haemolyticus genome.47
also detected in a few Danish isolates from this era (table 2).33 The distribution of SCCmec type IV provides some
In a recent communication by Enright,43 the same interesting clues concerning possible evolutionary
backgrounds were detected among an independent collection associations. In MRSA this mec element structure is seen in
of 394 epidemic MRSA isolates from 22 different countries three different genetic backgrounds, and SSCmec type IV was
characterised by MLST. The most frequent clonal complex I also seen in community-acquired MRSA6,39 and also in
described by this author appears to correspond to genetic coagulase-negative staphylococci (D C Oliveira, unpublished
background A and its variants described in this data).39 These findings suggest an enhanced mobility of this
communication. While MRSA with either ST22 or ST36 were mec element, perhaps explained by its smaller size. SCCmec
not detected among pandemic isolates in our collection, a few type IV has the same downstream structure as the SCCmec
MSSA isolates with ST36corresponding to our genetic type I. A high degree of similarity is also apparent upstream of
background Cwere detected among historically early mecA where both SCCmec I and IV have a deleted mecR1, an
MSSA from Denmark.33 What Enright43 describes as a fourth IS1272, and ccrAB flanked by two homologous sequences.
type of MRSA detected among isolates from the USA and However, the region between the chromosomal left junction
Europe presumably corresponds to our genetic background B and the upstream region of ccrABie, the gene pls and its
(MLST 1-4-1-4-12-1-10) characteristic of both the New flanking regions, close to 18 kb in sizeis missing in SCCmec
York/Japan and the paediatric clones of MRSA, which share a IV and was replaced by a variable DNA segment.37 The close
common MLST but may be distinguished by the distinct association of SCCmec type IV to SCCmec type I, which is
SCCmec type they carry (see table 4). present in the earliest MRSA isolates, together with its
presence in hospital-acquired and community-acquired
MRSA lineages and the acquisition of mec MRSA strains as well as in coagulase-negative staphylococci,
elements suggests that this mec element structure might be closely
Putting together all data one might propose important related to a putative precursor of the mec element.
inferences as to the evolutionary pathways through which
MRSA lineages could have emerged. MRSA strains have a Search strategies and selection criteria
strong clonal structure, by contrast with MSSA strains, Four types of references are quoted to provide context and
probably due to their shorter existence (four decades). The background information to the observations and
mec element, containing the meticillin-resistance hypotheses described in this communication: historical
determinant, seems to have been imported into the species of references to MRSA, MRSA in disease, and the changing
S aureus at multiple, yet restricted and independent, epidemiology of MRSA; references to novel molecular
occasions, as shown by the specific pattern of association typing techniques such as MLST and spaA typing;
between clonal types and SCCmec types. Horizontal transfer references to the origin, structure and putative functions of
of the mec element between different S aureus lineages could mec elements (SCCmec types); and references related to the
also have happened as suggested by the presence of SCCmec origins, epidemiological features and initial molecular
type IV in backgrounds A, B, and D, and SCCmec type II in characterisation of the large strain collection which was the
backgrounds B and C. However, horizontal transfer seems to source of epidemic MRSA clones described in our paper.
be a rare event and the spread of meticillin-resistance in
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Review Molecular evolution of MRSA
New trends in MRSA epidemiology backgrounds. However, both clones have low-level and
The specific pattern of association of SCCmec types and heterogeneous meticillin resistance and are frequently
MRSA clones opens the door to some speculations about isolated from patients with immature or compromised
possible contributions of the SCCmec itself to the immune systems (children and AIDS patients).30,5052 In a
pathogenic potential of MRSA strains. It has been proposed recent study, 22 of 28 patients with AIDS had MRSA
that the mec element might be a pathogenic and/or infections that were seen to belong to the USA Clone V.30 It
antibiotic-resistance island,22,48 capable of autonomous is tempting to consider the possibility that the pls deletion
excision provided by the chromosomal cassette recombinase contributes to the affinity of these strains for patients with
genes ccrA and ccrB present in every mec element.22 The mec weak immune systems.
element, besides being the carrier of mecA and its regulatory Several recent findings suggest that MRSA might be
genes (mecI and mecR1), also contains additional resistance emerging as a community pathogen5357 following perhaps
determinants in the form of integrated mobile elements the historic precedent of penicillin-resistant S aureus.58 A
(pUB110, pT181, pI258, Tn554, and Tn554). In this screening of 1001 S aureus isolates recovered from
respect the SCCmec structure clearly represents an colonisation sites of young and healthy people in a
antibiotic-resistance island. Other regions of the SCCmec community showed that more than 95% of the isolates were
might be more directly contributing to the pathogenic resistant to penicillin but only seven were MRSA.6 However,
potential of the S aureus cell. Such regions could be the pls five of these seven MRSA isolates were representatives of the
gene present in SCCmec type I and the kdp operon present in pandemic Iberian, Brazilian, and paediatric clones, giving
SCCmec type II. The pls gene, which codes for a large surface another reminder of the evolutionary process of these
protein, could suppress adhesion of the bacteria to their host staphylococcal lineages.
at some stages during infection.49 The kdp operon is an extra
copy of the potassium-transporter operon present elsewhere
Acknowledgments
in the genome,48 which could improve the colonisation
Some findings were made possible by the information available at the
and invasion processes of the host tissues. A possible MLST database (www.mlst.net) and the E-MSRA 16 genome-
association should be considered between the SCCmec sequencing project (www.sanger.ac.uk). Partial support for this
structure and the epidemiology of some MRSA clones. For study was provided by project POCTI/1999/ESP/34872 from
Fundao para a Cincia e Tecnologia, Lisbon, Portugal, awarded to
instance, SCCmec type IV, which differs mainly from HL, and by a grant from the US Public Health Service awarded to AT,
SCCmec type I by the absence of the pls gene and its flanking project RO1 AI37275. DCO was supported by a grant from Fundao
para a Cincia e Tecnologia, Lisbon, Portugal, and also from July 2001
regions, characterises both the paediatric MRSA clone and by a doctoral grant from Fundao Calouste Gulbenkian, Lisbon,
the USA clone V, which have completely different genetic Portugal.
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