title: Evolution of methicillin-resistant Staphylococcus aureus towards increasing resistance.
abstract: OBJECTIVE
  To elucidate the evolutionary history of Staphylococcus aureus clonal complex (CC) 8, which encompasses several globally distributed epidemic lineages, including hospital-associated methicillin-resistant S. aureus (MRSA) and the highly prevalent community-associated MRSA clone USA300.
  
  
  METHODS
  We reconstructed the phylogeny of S. aureus CC8 by mutation discovery at 112 genetic housekeeping loci from each of 174 isolates, sampled on five continents between 1957 and 2008. The distribution of antimicrobial resistance traits and of diverse mobile genetic elements was investigated in relation to the isolates' phylogeny.
  
  
  RESULTS
  Our analyses revealed the existence of nine phylogenetic clades within CC8. We identified at least eight independent events of methicillin resistance acquisition in CC8 and dated the origin of a methicillin-resistant progenitor of the notorious USA300 clone to the mid-1970s. Of the S. aureus isolates in our collection, 88% carried plasmidic rep gene sequences, with up to five different rep genes in individual isolates and a total of eight rep families. Mapping the plasmid content onto the isolates' phylogeny illustrated the stable carriage over decades of some plasmids and the more volatile nature of others. Strikingly, we observed trends of increasing antibiotic resistance during the evolution of several lineages, including USA300.
  
  
  CONCLUSIONS
  We propose a model for the evolution of S. aureus CC8, involving a split into at least nine phylogenetic lineages and a subsequent series of acquisitions and losses of mobile genetic elements that carry diverse virulence and antimicrobial resistance traits. The evolution of MRSA USA300 towards resistance to additional antibiotic classes is of major concern.
authors.affiliation: National Reference Centre for Staphylococci and Enterococci, Robert Koch Institute, Wernigerode Branch, Wernigerode, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Strommenger
authors.forename: Mette Damkjær
authors.initials: MD
authors.lastname: Bartels
authors.forename: Kevin
authors.initials: K
authors.lastname: Kurt
authors.forename: Franziska
authors.initials: F
authors.lastname: Layer
authors.forename: Susanne Mie
authors.initials: SM
authors.lastname: Rohde
authors.forename: Kit
authors.initials: K
authors.lastname: Boye
authors.forename: Henrik
authors.initials: H
authors.lastname: Westh
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Witte
authors.forename: Herminia
authors.initials: H
authors.lastname: De Lencastre
authors.forename: Ulrich
authors.initials: U
authors.lastname: Nübel
mesh_terms: D024901:Drug Resistance, Multiple, Bacterial; D019143:Evolution, Molecular; D005838:Genotype; D006801:Humans; D020071:Interspersed Repetitive Sequences; D055624:Methicillin-Resistant Staphylococcus aureus / Q000145:classification / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D010802:Phylogeny; D013203:Staphylococcal Infections / Q000382:microbiology*
keywords: MRSA; acquisition of resistance; mobile genetic elements; phylogeny; plasmids