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Relationship of agr Expression and Function with Virulence and Vancomycin Treatment Outcomes in Experimental Endocarditis due to Methicillin-Resistant ...

K Seidl, L Chen, AS Bayer, WA Hady... - Antimicrobial Agents ..., 2011 - Am Soc Microbiol ABSTRACT The accessory gene regulator (agr) locus has been shown to be important for virulence in several animal models of S. aureus infection. However, the role of agr in human infections, and specifically in antibiotic treatment is controversial. Interestingly, agr ...

The accessory gene regulator (agr) locus has been shown to be important for virulence in several animal models of S. aureus infection. However, the role of agr in human infections, and specifically in antibiotic treatment is controversial. Interestingly, agr dysfunction has been associated with reduced vancomycin responses. To systematically investigate the role of agr in virulence and treatment outcome in the context of endovascular infection, ten well-characterized vancomycin-susceptible MRSA bloodstream isolates (5 agr-I [CC45] and 5 agr-II [CC5]) were studied for: i) agr function; ii) RNAIII transcriptional profiles; iii) agr locus sequences; iv) intrinsic virulence and responses to vancomycin therapy in an experimental endocarditis (IE) model, and v) in vivo RNAIII expression. Significant differences in agr function (determined by δ-hemolysin activity) correlated with the time-point of RNAIII transcription (earlier RNAIII onset = increased agr function). Unexpectedly, four MRSA strains with strong δ-hemolysin activity exhibited significant resistance to vancomycin treatment in experimental IE. In contrast, five of six MRSA strains with weak or no δ-hemolysin activity were highly susceptible to vancomycin therapy in the IE model. agr sequence analyses showed no common single nucleotide polymorphism predictive of agr functionality. In vivo RNAIII expression in cardiac vegetations did not correlate with virulence or vancomycin treatment outcomes in the IE model. Inactivation of agr in two strains with strong δ-hemolysin activity did not affect virulence or in vivo efficacy of vancomycin. Our findings suggest that agr-dysfunction does not correlate with vancomycin treatment failures in experimental IE model in two distinct MRSA genetic backgrounds.