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The discovery of communication systems regulating bacterial virulence has afforded a novel opportunity to control infectious bacteria without interfering with their growth. In this paper the authors describe the effect of subinhibitory concentrations of phenyl-lactic acid (PLA) on the pathogenicity of Staphylococcus aureus in holoxenic mice. The animals were inoculated by oral (p.o.), intranasal (i.n.), intravenous (i.v.) and intraperitoneal (i.p.) routes with S. aureus wild and PLA-treated cultures. The mice were followed up during 16 days after infection and the body weight, mortality and morbidity rate were measured every day. The microbial charge was studied by viable cell counts in lungs, spleen, intestinal mucosa and blood. The present study has proved that PLA, besides its microbicidal activity, could attenuate in subinhibitory concentrations the virulence and pathogenicity of S. aureus strains, as demonstrated by in vivo holoxenic mouse infection experimental model. Our results are accounting for the hypothesis that subinhibitory concentrations of PLA, which are not affecting the bacterial cell viability, are probably interfering with the intracellular communication and the sequential and coordinated expression of different virulence factors, altering the success of this pathogen in the colonization of sensitive hosts and the development of an infectious process.