Relationship ofagrExpression and Function with Virulence and Vancomycin Treatment Outcomes in Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus

Abstract

ABSTRACTThe accessory gene regulator (agr) locus has been shown to be important for virulence in several animal models ofStaphylococcusaureusinfection. However, the role ofagrin human infections, and specifically in antibiotic treatment, is controversial. Interestingly,agrdysfunction has been associated with reduced vancomycin responses. To systematically investigate the role ofagrin virulence and treatment outcome in the context of endovascular infection, 10 well-characterized vancomycin-susceptible methicillin-resistantS. aureus(MRSA) bloodstream isolates (5agr-I[clonal complex 45, or CC45] and 5agr-II[CC5]) were studied for (i)agrfunction, (ii) RNAIII transcriptional profiles, (iii)agrlocus sequences, (iv) intrinsic virulence and responses to vancomycin therapy in an experimental infective endocarditis (IE) model, and (v)in vivoRNAIII expression. Significant differences inagrfunction (determined by delta-hemolysin activity) correlated with the time point of RNAIII transcription (earlier RNAIII onset equals increasedagrfunction). Unexpectedly, four MRSA strains with strong delta-hemolysin activities exhibited significant resistance to vancomycin treatment in experimental IE. In contrast, five of six MRSA strains with weak or no delta-hemolysin activity were highly susceptible to vancomycin therapy in the IE model.agrsequence analyses showed no common single-nucleotide polymorphism predictive ofagrfunctionality.In vivoRNAIII expression in cardiac vegetations did not correlate with virulence or vancomycin treatment outcomes in the IE model. Inactivation ofagrin two strains with strong delta-hemolysin activity did not affect virulence or thein vivoefficacy of vancomycin. Our findings suggest thatagrdysfunction does not correlate with vancomycin treatment failures in this experimental IE model in two distinct MRSA genetic backgrounds.