Treatment of Staphylococcus aureus with environmentally relevant concentrations of triclosan activates SaeRS-dependent virulence factor expression.

In the human pathogen Staphylococcus aureus, the two-component regulatory system SaeRS contributes to the expression of numerous virulence factors essential for pathogenesis. The kinase and phosphatase activities of SaeS are stimulated by several host and physiological signals, resulting in increased phosphorylation of the transcription factor SaeR and increased transcriptional activity of regulated promoters. It was recently demonstrated that the accumulation of fatty acids negatively impacts SaeS activity, decreasing titers of phosphorylated SaeP and transcriptional output. Triclosan is an effective antimicrobial that has been integrated as an ingredient in a variety of healthcare and consumer products. The chlorinated compound is recalcitrant to natural or biological transformations, resulting in environmental accumulation. At low concentrations, triclosan is a bacteriostatic inhibitor of enoyl-acetyl carrier protein reductase (FabI) of the type II fatty acid synthesis system (FASII), which is necessary for the elongation and synthesis of fatty acids. Herein, we demonstrate that the treatment of S. aureus with a growth-permissive concentration of triclosan alters the titers of cell-associated fatty acids and thereby functions as an activator of SaeRS. Triclosan-dependent activation of SaeRS subsequently resulted in increased transcription and expression of genes that code for virulence factors. These phenotypes are chemically reversed by the exogenous addition of oleic acid, which inactivates SaeRS, and genetically reversed by crippling the FakAB fatty acid kinase system, which generates phosphorylated fatty acids for incorporation into phospholipids. These findings present implications for the widespread use of triclosan as an antimicrobial agent in household products and its role as a persistent environmental pollutant.