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      Methicillin-resistant Staphylococcus aureus emerged long before the introduction of methicillin into clinical practice

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          Abstract

          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 SCC mec 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 SCC mec was acquired. MRSA emerged in the mid-1940s, following the acquisition of an ancestral type I SCC mec 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.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13059-017-1252-9) contains supplementary material, which is available to authorized users.

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          Most cited references25

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          The evolutionary history of methicillin-resistant Staphylococcus aureus (MRSA).

          Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of hospital-acquired infections that are becoming increasingly difficult to combat because of emerging resistance to all current antibiotic classes. The evolutionary origins of MRSA are poorly understood, no rational nomenclature exists, and there is no consensus on the number of major MRSA clones or the relatedness of clones described from different countries. We resolve all of these issues and provide a more thorough and precise analysis of the evolution of MRSA clones than has previously been possible. Using multilocus sequence typing and an algorithm, BURST, we analyzed an international collection of 912 MRSA and methicillin-susceptible S. aureus (MSSA) isolates. We identified 11 major MRSA clones within five groups of related genotypes. The putative ancestral genotype of each group and the most parsimonious patterns of descent of isolates from each ancestor were inferred by using BURST, which, together with analysis of the methicillin resistance genes, established the likely evolutionary origins of each major MRSA clone, the genotype of the original MRSA clone and its MSSA progenitor, and the extent of acquisition and horizontal movement of the methicillin resistance genes. Major MRSA clones have arisen repeatedly from successful epidemic MSSA strains, and isolates with decreased susceptibility to vancomycin, the antibiotic of last resort, are arising from some of these major MRSA clones, highlighting a depressing progression of increasing drug resistance within a small number of ecologically successful S. aureus genotypes.
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            A new class of genetic element, staphylococcus cassette chromosome mec, encodes methicillin resistance in Staphylococcus aureus.

            We have previously shown that the methicillin-resistance gene mecA of Staphylococcus aureus strain N315 is localized within a large (52-kb) DNA cassette (designated the staphylococcal cassette chromosome mec [SCCmec]) inserted in the chromosome. By sequence determination of the entire DNA, we identified two novel genes (designated cassette chromosome recombinase genes [ccrA and ccrB]) encoding polypeptides having a partial homology to recombinases of the invertase/resolvase family. The open reading frames were found to catalyze precise excision of the SCCmec from the methicillin-resistant S. aureus chromosome and site-specific as well as orientation-specific integration of the SCCmec into the S. aureus chromosome when introduced into the cells as a recombinant multicopy plasmid. We propose that SCCmec driven by a novel set of recombinases represents a new family of staphylococcal genomic elements.
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              Structural comparison of three types of staphylococcal cassette chromosome mec integrated in the chromosome in methicillin-resistant Staphylococcus aureus.

              The beta-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.
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                Author and article information

                Contributors
                44 1334 463504 , mtgh@st-andrews.ac.uk
                Journal
                Genome Biol
                Genome Biol
                Genome Biology
                BioMed Central (London )
                1474-7596
                1474-760X
                20 July 2017
                20 July 2017
                2017
                : 18
                : 130
                Affiliations
                [1 ]ISNI 0000 0001 0721 1626, GRID grid.11914.3c, , School of Medicine, University of St Andrews, ; St Andrews, KY16 9TF UK
                [2 ]ISNI 0000 0004 0397 2876, GRID grid.8241.f, School of Medicine, , University of Dundee, ; Dundee, DD1 9SY UK
                [3 ]ISNI 0000 0001 2196 8713, GRID grid.9004.d, , Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, National Infection Service, Public Health England, ; Colindale, UK
                [4 ]ISNI 0000 0004 0606 5382, GRID grid.10306.34, , The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, ; Hinxton, Cambridge, UK
                [5 ]ISNI 0000 0004 0646 8202, GRID grid.411905.8, Department of Clinical Microbiology, , Hvidovre University Hospital, ; Hvidovre, Denmark
                [6 ]ISNI 0000 0001 0674 042X, GRID grid.5254.6, , Institute of Clinical Medicine, University of Copenhagen, ; Copenhagen, Denmark
                [7 ]ISNI 0000 0001 2166 1519, GRID grid.134907.8, , Laboratory of Microbiology and Infectious Diseases, The Rockefeller University, ; New York, USA
                [8 ]ISNI 0000000121511713, GRID grid.10772.33, , Laboratory of Molecular Genetics, Instituto de Tecnologia Química e Biológica António Xavier (ITQB), Universidade Nova de Lisboa, ; Oeiras, Portugal
                Article
                1252
                10.1186/s13059-017-1252-9
                5517843
                28724393
                c1be0e4f-1573-4288-b127-cb2e3faf1ed4
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 9 April 2017
                : 7 June 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100004440, Wellcome Trust;
                Award ID: 097831/Z/11/Z
                Award ID: 098051
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Genetics
                staphylococcus aureus,mrsa,antibiotic resistance
                Genetics
                staphylococcus aureus, mrsa, antibiotic resistance

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