title: Early agr activation correlates with vancomycin treatment failure in multi-clonotype MRSA endovascular infections.
abstract: OBJECTIVE
  Persistent MRSA infections are especially relevant to endovascular infections and correlate with suboptimal outcomes. However, the virulence signatures of Staphylococcus aureus that drive such persistence outcomes are not well defined. In the current study, we investigated correlations between accessory gene regulator (agr) activation and the outcome of vancomycin treatment in an experimental model of infective endocarditis (IE) due to MRSA strains with different agr and clonal complex (CC) types.
  
  
  METHODS
  Twelve isolates with the four most common MRSA CC and agr types (CC5-agr II, CC8-agr I, CC30-agr III and CC45-agr I) were evaluated for heterogeneous vancomycin-intermediate S. aureus (hVISA), agr function, agrA and RNAIII transcription, agr locus sequences, virulence and response to vancomycin in the IE model.
  
  
  RESULTS
  Early agr RNAIII activation (beginning at 2 h of growth) in parallel with strong δ-haemolysin production correlated with persistent outcomes in the IE model following vancomycin therapy. Importantly, such treatment failures occurred across the range of CC/agr types studied. In addition, these MRSA strains: (i) were vancomycin susceptible in vitro; (ii) were not hVISA or vancomycin tolerant; and (iii) did not evolve hVISA phenotypes or perturbed δ-haemolysin activity in vivo following vancomycin therapy. Moreover, agr locus sequence analyses revealed no common point mutations that correlated with either temporal RNAIII transcription or vancomycin treatment outcomes, encompassing different CC and agr types.
  
  
  CONCLUSIONS
  These data suggest that temporal agr RNAIII activation and agr functional profiles may be useful biomarkers to predict the in vivo persistence of endovascular MRSA infections despite vancomycin therapy.
authors.affiliation: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Wessam
authors.initials: W
authors.lastname: Abdelhady
authors.affiliation: Public Health Research Institute, NJMS-Rutgers University, Newark, NJ, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Bayer
authors.affiliation: University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Kati
authors.initials: K
authors.lastname: Seidl
authors.affiliation: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Yeaman
authors.affiliation: Public Health Research Institute, NJMS-Rutgers University, Newark, NJ, USA.
authors.forename: Barry N
authors.initials: BN
authors.lastname: Kreiswirth
authors.affiliation: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA David Geffen School of Medicine at UCLA, Los Angeles, CA, USA yxiong@ucla.edu.
authors.forename: Yan Q
authors.initials: YQ
authors.lastname: Xiong
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D004696:Endocarditis / Q000188:drug therapy* / Q000382:microbiology; D020869:Gene Expression Profiling; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D011817:Rabbits; D017422:Sequence Analysis, DNA; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D015534:Trans-Activators / Q000235:genetics*; D015533:Transcriptional Activation; D017211:Treatment Failure; D014774:Virulence
chemical_list: C095698:Agr protein, Staphylococcus aureus; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D015534:Trans-Activators
keywords: antibiotics; bacteria; resistance