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, 18 (1), 130

Methicillin-resistant Staphylococcus Aureus Emerged Long Before the Introduction of Methicillin Into Clinical Practice


Methicillin-resistant Staphylococcus Aureus Emerged Long Before the Introduction of Methicillin Into Clinical Practice

Catriona P Harkins et al. Genome Biol.


Background: The spread of drug-resistant bacterial pathogens poses a major threat to global health. It is widely recognised that the widespread use of antibiotics has generated selective pressures that have driven the emergence of resistant strains. Methicillin-resistant Staphylococcus aureus (MRSA) was first observed in 1960, less than one year after the introduction of this second generation beta-lactam antibiotic into clinical practice. Epidemiological evidence has always suggested that resistance arose around this period, when the mecA gene encoding methicillin resistance carried on an SCCmec element, was horizontally transferred to an intrinsically sensitive strain of S. aureus.

Results: Whole genome sequencing a collection of the first MRSA isolates allows us to reconstruct the evolutionary history of the archetypal MRSA. We apply Bayesian phylogenetic reconstruction to infer the time point at which this early MRSA lineage arose and when SCCmec was acquired. MRSA emerged in the mid-1940s, following the acquisition of an ancestral type I SCCmec element, some 14 years before the first therapeutic use of methicillin.

Conclusions: Methicillin use was not the original driving factor in the evolution of MRSA as previously thought. Rather it was the widespread use of first generation beta-lactams such as penicillin in the years prior to the introduction of methicillin, which selected for S. aureus strains carrying the mecA determinant. Crucially this highlights how new drugs, introduced to circumvent known resistance mechanisms, can be rendered ineffective by unrecognised adaptations in the bacterial population due to the historic selective landscape created by the widespread use of other antibiotics.

Keywords: Antibiotic resistance; MRSA; Staphylococcus aureus.


Fig. 1
Fig. 1
Population structure of historic MRSA isolates. a Maximum likelihood tree of historic MRSA isolates. The tree was built using a maximum likelihood method using SNPs from the core genome of 209 isolates. Included in the phylogeny is the COL reference isolate to which the sequence reads were mapped. The tree is rooted with RH12000692_7401696 as an outgroup; this is a CC8 isolate and is a triple locus variant of ST250. Tree branches are coloured according to their ancestral sequence type population; blue branches indicate the ST250 population and green branches the ST247 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
Fig. 2
Fig. 2
Distribution of antibiotic resistance determinants in the archetypal MRSA clone. A maximum likelihood tree of historic MRSA isolates (n = 209) plus the COL reference is displayed on the left, and the panels on the right indicate dates of isolation (coloured according to year; see key below for years), and the presence (purple boxes) and absence (white space) of genetic determinants responsible for antibiotic resistance in the genomes of the isolates. 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). The antibiotics linked to the genetic determinants for the acquired genes are: β-lactams, blaZ and mecA; chloramphenicol, catA1, catA2, and catA3; erythromycin, ermA; clindamycin, linA; aminoglycosides, aacA-aphD, aad9, aadD, aph3A, and str; tetracycline, tetM and tetK; disinfectants, qacA and qacC. 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 406 (P404L) of the transcription elongation factor fusA; trimethoprim, substitution of an tyrosine for a phenylalanine at residue 99 (F99Y) of the dihydrofolate reductase dfrA. Sixteen isolates lacked complete type I SCCmec elements, 4 of which contained internal deletions in the SCCmec element but retained the mecA gene
Fig. 3
Fig. 3
Diversity and distribution of SCCmec type I elements in the archetypal MRSA population. a Parsimonious minimal spanning tree of SCCmec type I elements present in the archetypal MRSA isolates present in the clade credibility tree in b. The tree is built with core SNPs identified in the SCCmec type I elements, and excludes SNP in the pls gene that were predicted to have arisen by recombination. 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 SCCmec element. The sizes of the circles illustrate the relative sizes of the genotype populations. The key below the tree describes the canonical SNPs differentiating SCCmec type I genotypes and the number of variants with that genotype. b Maximum clade credibility tree of the archetypal MRSA clone population based on BEAST analysis. Tips of the tree are constrained by isolation dates; the time scale is shown below the tree. The tree is built with core genome SNPs from a subset of the total collection’s isolates (n = 122), which had precise dates of isolation, and whose origins could be linked back to the original submission documentation. The branches of the tree are coloured according to the genotype of the SCCmec 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 SCCmec element, which is predicted to reflect loss of the element. An arrow indicates the point in the phylogenetic reconstruction where an ancestral type I SCCmec element was acquired. The root of the tree corresponds to the basal node of the ST250/ST247 population in Fig. 1 rooted by the RH12000692_7401696 outgroup. From the analysis the estimated mutation rate of population is 1.8 × 10−6 SNPs/site/year. This substitution rate falls within the reported ranges of multiple successful S. aureus lineages [31] and therefore it is unlikely likely that long-term storage of the isolates has created any temporal artefacts
Fig. 4
Fig. 4
The time to most recent common ancestor (TMRCA) of the archetypal MRSA isolates under various combinations of clock and population model in BEAST. Plots showing mean (dots) TMRCA and 95% highest posterior density for the TMRCA are indicated. The dates of introduction of penicillin and methicillin into clinical use in the UK are indicated with green and red lines, respectively

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