On this page: History Transmission History Methicillin-resistant strains of Staphylococcus aureus MRSA were first recognized in , one year after the antibiotic methicillin was introduced for treating S. MRSA is resistant to unable to be killed by all beta-lactam antibiotics. This includes all penicillins e. For the next two decades most MRSA infections occurred in persons who had contact with hospitals or other health care settings health care-associated MRSA.
However, MRSA infections are now seen in previously healthy persons. The tree was built using a maximum likelihood method using SNPs from the core genome of isolates. Included in the phylogeny is the COL reference isolate to which the sequence reads were mapped. Tree branches are coloured according to their ancestral sequence type population; blue branches indicate the ST population and green branches the ST population. Isolates from Denmark are highlighted in blue shading and isolates described in the Jevons study are outlined in the dashed box , and a zoomed in view of the phylogeny is displayed in b.
The coloured branch labels indicate the three individuals who supplied the original isolates in the Jevons study. Highlighted in the expanded view Fig. The isolation source and resistance profiles of these isolates are shown in Additional file 2 : Table S2. These isolates are genetically very closely related, differing by seven SNPs only.
Present within this cluster are additional isolates from the Public Health England collection originating between and Full epidemiological data are not available for these, but two of these isolates were identified in the same region as the hospital where the original Jevons study isolates originated.
The genetic distance between isolates and their phylogenetic relationships suggests there was transmission within the hospital between patients A and C and nurse B, and that they were also transmitted beyond the hospital as part of a local outbreak. Although all of the Jevons isolates are confined to a single clade, other isolates from the early s are distributed throughout the entire phylogeny Fig.
This suggests that the earliest MRSA circulating in the UK were not from a single recently emerged clone, but were representatives of an established population. These derive from onwards, and include the youngest isolates within the collection from the late s.
The Danish isolates are found in three clusters distributed throughout the phylogeny Fig. Distribution of antibiotic resistance determinants in the archetypal MRSA clone. The identity of genetic determinants are listed at the top and divided into acquired genes red text ; left hand side , and core mutations green text ; right hand side.
And for the core gene mutations are: streptomycin substitution of arginine for a lysine at residue 56 K56R of the ribosomal protein rpsL ; fusidic acid, substitution of a proline for a leucine at residue PL of the transcription elongation factor fusA ; trimethoprim, substitution of an tyrosine for a phenylalanine at residue 99 F99Y of the dihydrofolate reductase dfrA.
The type I element carries mecA as its only resistance gene in combination with a truncated gene encoding the MecRI regulatory proteins together known as a class B mec gene complex with type 1 chromosomal recombinases ccrA1 and ccrB1.
The original description of SCC mec type I identified the presence of a frameshift mutation in ccrB1 which disrupts the translation of this site-specific recombinase [ 13 ]; the mutation occurs after codon and is caused by a single base deletion in a poly-A hexamer resulting in a pentamer sequence.
The remaining 16 isolates lacking complete SCC mec elements were distributed throughout the phylogeny, suggesting that these represent methicillin-sensitive S. In addition to methicillin resistance, the first MRSA described were also resistant to penicillin, streptomycin and tetracycline [ 3 ]. Analysis of the genomes of these isolates identified blaZ and tetK genes conferring resistance to penicillin and tetracycline, respectively, but failed to identify the str, aadE or aad9 genes associated with streptomycin resistance in S.
In the absence of an acquired resistance gene, the core genome was examined for mutations potentially responsible for resistance to streptomycin. In Mycobacterium tuberculosis , mutations in the ribosomal protein RpsL were shown to confer streptomycin resistance, including the substitution of an arginine for a lysine residue at residue 43 [ 14 ].
Alignment of the M. Comparison with RpsL sequences in the public sequence databases showed that in S. This demonstrates that the non-synonymous substitution resulting in an arginine for a lysine residue at residue 56 K56R occurred most likely very early during emergence of the archetypal MRSA population.
In silico analysis of the resistomes of the isolates revealed genetic resistance determinants to numerous other antibiotics, including penicillin blaZ , erythromycin ermA and linA , kanamycin aadD , gentamicin and kanamycin aacA - aphD , spectinomycin and streptomycin aad9 , and chloramphenicol catA1 , catA2 and catA3 , fusidic acid fusA PL and trimethoprim dfrA F99Y , as well as genes associated with decreased susceptibility to disinfectants qacA and qacC.
The frequency and widespread dispersal of these determinants reveal the strong selective pressure exerted by antibiotics on the archetypal MRSA clone over an extensive period. Examining their distribution in the context of the phylogeny shows that some of these traits have been co-acquired Fig. To determine if the methicillin resistance emerged once or multiple times in the archetypal MRSA population, we examined the variation within the SCC mec type I elements.
In total, variant sites were identified in elements present in the collection. Analysis of the distribution of the variation within the elements suggested that some could be attributed to homologous recombination. Excluding these predicted recombination regions, 39 core variants sites across The maximum SNP distance distinguishing any two elements was eight SNPs, and phylogenetic analysis revealed that the elements present in the historic MRSA clone were closely related Additional file 3 : Figure S1 and shared a common evolutionary origin.
Our analysis of the evolutionary events surrounding the emergence of methicillin resistance in the archetypal MRSA lineage focused on a subset of isolates that had precise dates and places of origin which could be linked to original submission records Additional file 2 : Table S1. This enabled us to generate a robust Bayesian phylogeny and temporal calibration. All of the canonical SNPs associated with the SCC mec genotypes could be singularly mapped onto nodes of the core phylogeny, suggesting that the variation observed in the SCC mec elements had occurred during expansion of the ST and ST populations.
On the basis of this, we propose that a type I SCC mec element was acquired once in a single primordial development of methicillin resistance Fig. In total, ten genotypes were observed, and the genetic events that distinguish each genotype from the founder genotype are indicated. The tree is centred on the majority genotype inferred as the founder population, and colour-coded according to their genotype.
Black asterisks indicate isolates that lack the type I SCC me c element. The sizes of the circles illustrate the relative sizes of the genotype populations. The key below the tree describes the canonical SNPs differentiating SCC mec type I genotypes and the number of variants with that genotype. Tips of the tree are constrained by isolation dates; the time scale is shown below the tree. The branches of the tree are coloured according to the genotype of the SCC mec type I element present in that strain illustrated in a.
Internal branches are coloured according to parsimonious reconstruction of the predicted genotype. Where terminal branches are black and highlighted by a black asterisk , this indicates the absence of an SCC mec element, which is predicted to reflect loss of the element. An arrow indicates the point in the phylogenetic reconstruction where an ancestral type I SCC mec element was acquired. From the analysis the estimated mutation rate of population is 1.
This substitution rate falls within the reported ranges of multiple successful S. In our Bayesian phylogenetic analysis of the core genome SNPs we utilized a range of population and clock model combinations.
The combination of an exponential population and relaxed-log normal clock model was found to be the best fit to our data based on Bayes factors using the harmonic mean estimator. The dates of introduction of penicillin and methicillin into clinical use in the UK are indicated with green and red lines , respectively.
This historic collection provides unique insights into of the evolution of the first MRSA lineage. Preserved for decades in their original freeze-dried state, this large collection of strains representing the earliest MRSA clone has allowed us to reconstruct the evolutionary events leading to the emergence of MRSA.
Using whole genome sequencing we have been able to shed light on the time when SCC mec first entered into S. A single entry of mecA followed by its evolution within the recipient background has been suggested [ 17 ].
In order to clarify this we examined the variation present within the SCC mec elements in isolates throughout the population. The variation seen within SCC mec is predominantly in the pls gene, which has been described before [ 18 ].
Functionality of this kDa cell wall-anchored CWA protein remains unclear, but its expression has been shown to reduce adhesion to host proteins as well as decrease invasiveness [ 19 ]. As noted in other lineages the CWA proteins are subject to diversifying selection and exhibit diversity between and within S.
Removal of this variation reveals that the evolutionary history of the SCC mec elements was congruent with that of the strains carrying them, which points towards a single acquisition, rather than multiple or recurrent horizontal transmissions. Supporting this hypothesis is the observation of a mutation in ccrB1 gene of the SCC mec type I element.
The recombinase genes are required for both integration and excision from the chromosome. Given that all the isolates in this collection have this frameshift mutation, this strongly supports the conclusions of the phylogenetic analysis, namely that a type I SCC mec was acquired once in the ST background, and then became fixed in the population due to defective recombinase apparatus that precluded excision.
One of the questions we sought to address in this study was what were the temporal events surrounding the emergence of MRSA. With the first reports of MRSA occurring only after introduction of methicillin in the UK in and Denmark in it seemed reasonable to conclude that resistance arose after the first clinical use of the drug, and resistance therefore developed in S.
However, the results presented in this communication are not consistent with this conclusion, since the gene bestowing methicillin resistance was likely to have been acquired in the mids. Within 4 years of the introduction of penicillin for the treatment of staphylococcal infections, the first penicillin-resistant S. Whilst the main genetic determinant associated with penicillin resistance in S. In the sequenced collection blaZ is widely distributed, albeit at a lower frequency than mecA Based on the temporal calibration of the acquisition of mecA , it appears likely that methicillin resistance in S.
Thus, it was the widespread use of penicillin, rather than methicillin, that was the driver for the emergence in the archaic MRSA clone. Several of the antibiotics, such as tetracycline, are prescribed in far lower amounts today in human medicine than in the s and s, and resistance to these antibiotics in contemporary S. In a prescient study examining the antibiotic consumption and rates of resistance in a hospital in the US in the s, Bauer et al.
In addition to methicillin and tetracycline resistances, a key phenotypic marker of the archaic MRSA clone was non-susceptibility to streptomycin. In our analysis we identified a mutation predicted to confer streptomycin resistance occurring on the same branch of the tree in which we mapped the acquisition of the SCC mec element. This finding suggests that methicillin and streptomycin resistance both emerged in the archetypal MRSA progenitor population around the same time.
Discovered in the early s, streptomycin was demonstrated to have activity against Gram-positive pathogens, and was used in the UK in during the first ever randomized clinical trials studying the efficacy of streptomycin in the treatment of pulmonary tuberculosis [ 28 , 29 ].
It therefore appears that the first MRSA clone emerged, and developed resistance to two of the earliest antibiotics—streptomycin and penicillin—almost immediately after the S. At the time of its discovery, the incidence of MRSA in the general population is likely to have been very low. This is demonstrated by the fact that screening of over samples at Public Health England yielded only three methicillin-resistant isolates.
Therefore, it is likely that when methicillin was introduced to circumvent penicillin resistance in S. This study highlights the unintended consequences of widespread antibiotic use, and how when new drugs are introduced to bypass known resistance mechanisms, they may already be rendered ineffective due to unrecognised adaptations accrued in response to prior selective pressures exerted by other antibiotics.
This remains one of the many challenges in tackling the growing problem of AMR and serves to emphasise the importance of continual surveillance of pathogen populations for evidence of emerging adaptations and resistance patterns in the context of prescribing practice. Two hundred and nine isolates derived from the culture collections of Staphylococcus aureus reference laboratory, Public Health England, and isolates originating from the Statens Serum Institute collected and analysed by Profs Tomasz, Westh and de Lencastre.
Isolates from the Public Health England collection were all retrieved from the original freeze-dried cultures put down in the s. A record of the number of sub-cultures prior to freeze-drying, or post-isolate recovery, was not available, but it is known that the isolates were not repeatedly sub-cultured over the last 50 years.
In , surgeon Alexander Ogston first discovered S. MRSA eventually spread across the world and the first U. MRSA later became resistant to all beta-lactams — penicillin-like antibiotics that include penicillin, methicillin, amoxicillin and oxacillin.
MRSA became known as an endemic pathogen across hospitals, particularly in large urban university hospitals. During this time, those at highest risk for CA-MRSA included athletes, military recruits, incarcerated people, emergency room patients, people with HIV and men who have sex with men.
An experimental vaccine that targeted the two most common surface antigens of S. However, the vaccine failed in a follow-up phase 3 trial. Other vaccines are currently in the early stages of development.
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