Subinhibitory Concentrations of Fusidic Acid May Reduce the Virulence of S. aureus by Down-Regulating sarA and saeRS to Reduce Biofilm Formation and α-Toxin Expression

Abstract

<i>Staphylococcus aureus</i> is an important pathogen in hospital and community infections. Fusidic acid is particularly effective in treating skin and wound infections caused by staphylococci. The purpose of our study was to clarify the effect of fusidic acid on the biofilm formation and α-toxin expression of <i>S. aureus</i> at subinhibitory concentrations [1/64, 1/32, and 1/16 × minimum inhibitory concentration (MIC)]. A total of 504 genes greater than a twofold or less than twofold change in expression of <i>S. aureus</i> effected by subinhibitory concentrations of fusidic acid were found, including 232 up-regulated genes and 272 down-regulated genes, which were determined by transcriptome sequencing. Our results showed subinhibitory concentrations of fusidic acid significantly inhibited the expression of <i>hla</i>, <i>spa</i>, <i>icaA</i>, and <i>cidA</i> at the mRNA level in clinical <i>S. aureus</i> strains tested. And subinhibitory concentrations of fusidic acid can significantly reduce the hemolysis activity and α-toxin production of <i>S. aureus</i>. In addition, the subinhibitory concentrations of fusidic acid significantly inhibited biofilm formation, autolysis, cell aggregation, and polysaccharide intercellular adhesin (PIA) production of <i>S. aureus</i>. Moreover, fusidic acid effectively reduces the damage of mouse skin lesion area. Furthermore, fusidic acid reduced the expression of the two-component regulatory system <i>saeRS</i> and staphylococcal accessory gene regulator (<i>sarA</i>). In conclusion, our results suggested that the subinhibitory concentrations of fusidic acid may reduce the virulence of <i>S. aureus</i> by down-regulating <i>sarA</i> and <i>saeRS</i> to reduce biofilm formation and α-toxin expression, which will provide a theoretical basis for the clinical treatment of <i>S. aureus</i> infection. This is the first report that fusidic acid has an inhibitory effect on the virulence of <i>S. aureus</i>, and this broadens the clinical application of fusidic acid.