Sequential evolution of virulence and resistance during clonal spread of community-acquired methicillin-resistant Staphylococcus aureus

Richard Copin, William E. Sause, Yi Fulmer, Divya Balasubramanian, Sophie Dyzenhaus, Jamil M. Ahmed, Krishan Kumar, John Lees, Anna Stachel, Jason C. Fisher, Karl Drlica, Michael Phillips, Jeffrey N. Weiser, Paul J. Planet, Anne Catrin Uhlemann, Deena R. Altman, Robert Sebra, Harm van Bakel, Jennifer Lighter, Victor J. TorresBo Shopsin

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

The past two decades have witnessed an alarming expansion of staphylococcal disease caused by community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). The factors underlying the epidemic expansion of CA-MRSA lineages such as USA300, the predominant CA-MRSA clone in the United States, are largely unknown. Previously described virulence and antimicrobial resistance genes that promote the dissemination of CA-MRSA are carried by mobile genetic elements, including phages and plasmids. Here, we used high-resolution genomics and experimental infections to characterize the evolution of a USA300 variant plaguing a patient population at increased risk of infection to understand the mechanisms underlying the emergence of genetic elements that facilitate clonal spread of the pathogen. Genetic analyses provided conclusive evidence that fitness (manifest as emergence of a dominant clone) changed coincidently with the stepwise emergence of (i) a unique prophage and mutation of the regulator of the pyrimidine nucleotide biosynthetic operon that promoted abscess formation and colonization, respectively, thereby priming the clone for success; and (ii) a unique plasmid that conferred resistance to two topical microbio-cides, mupirocin and chlorhexidine, frequently used for decolonization and infection prevention. The resistance plasmid evolved through successive incorporation of DNA elements from non-S. aureus spp. into an indigenous cryptic plasmid, suggesting a mechanism for interspecies genetic exchange that promotes antimicrobial resistance. Collectively, the data suggest that clonal spread in a vulnerable population resulted from extensive clinical intervention and intense selection pressure toward a pathogen lifestyle that involved the evolution of consequential mutations and mobile genetic elements.

Original languageEnglish
Pages (from-to)1745-1754
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number5
DOIs
StatePublished - 29 Jan 2019

Keywords

  • Antimicrobial resistance
  • Evolution
  • MRSA
  • Virulence

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