Sub-inhibitory concentrations of tigecycline could attenuate the virulence of <i>Staphylococcus aureus</i> by inhibiting the product of α-toxin

<i>Staphylococcus aureus</i> (<i>S. aureus</i>) infection is a serious threat to global health. This study aimed to investigate the anti-virulence efficacy of tigecycline against <i>S. aureus</i>. We used highly virulent <i>S. aureus</i> strains SA75 and JP30 to evaluate the effect of tigecycline on virulence, both of them isolated from the clinic. The MIC value of tigecycline against SA75 was 0.125 µg/mL, and that against JP30 was 0.25 µg/mL. Tigecycline did not affect the growth ability of bacteria at 0.015 µg/mL. Thus, subsequent discussions will focus on the effect of antibiotics at the latter subinhibitory concentrations that did not affect growth. First, the sub-MICs of tigecycline not only enhanced the sensitivity of <i>S. aureus</i> to oxidants and human whole blood but also weakened the hemolytic activity and cell adhesion level of <i>S. aureus</i>. Second, it undermined the survival of <i>S. aureus</i> in RAW264.7 and attenuated the macrophage inflammatory response induced by <i>S. aureus</i>. On the contrary, tigecycline decreased the hemolytic activity, as well as the skin abscess formation and bacterial burden in mice. Most importantly, it significantly decreased the expression of <i>hla</i>, <i>hlgB</i>, <i>hlgC</i>, <i>spa</i>, <i>sbi</i>, <i>saeR</i>, <i>sak</i>, <i>tst</i>, and <i>coa</i> genes by RT-qPCR and the protein expression of α-toxin. Altogether, the sub-MICs of tigecycline might be a promising agent to attenuate the virulence of <i>S. aureus</i> and its host immune response by inhibiting the SaeRS two-component system and the product of α-toxin.IMPORTANCEIn this study, the sub-MICs of tigecycline decreased the resistance of <i>S. aureus</i> to oxidants and human whole blood. Moreover, tigecycline weakened the cell adhesion level of <i>S. aureus</i> and skin abscess formation in mice by reducing bacterial burden. Remarkably, tigecycline decreased the hemolytic activity and significantly downregulated the expression of various virulence genes and α-toxin. This research highlighted that the sub-MICs of tigecycline might be a promising agent to attenuate the virulence of <i>S. aureus</i> by inhibiting the product of α-toxin.