Small-molecule compound SYG-180-2-2 attenuates Staphylococcus aureus virulence by inhibiting hemolysin and staphyloxanthin production

Abstract

Multi-drug resistant <i>Staphylococcus aureus</i> infection is still a serious threat to global health. Therefore, there is an urgent need to develop new antibacterial agents based on virulence factor therapy to overcome drug resistance. Previously, we synthesized SYG-180-2-2 (C₂₁H₁₆N₂OSe), an effective small molecule compound against biofilm. The aim of this study was to investigate the anti-virulence efficacy of SYG-180-2-2 against <i>Staphylococcus aureus</i>. MIC results demonstrated no apparent antibacterial activity of the SYG-180-2-2. The growth curve assay showed that SYG-180-2-2 had nonlethal effect on <i>S. aureus</i>. Besides, SYG-180-2-2 strongly inhibited the hemolytic activity and staphyloxanthin synthesis in <i>S. aureus</i>. Inhibition of staphyloxanthin by SYG-180-2-2 enhanced the sensitivity of <i>S. aureus</i> to oxidants and human whole blood. In addition, SYG-180-2-2 significantly decreased the expression of <i>saeR</i>-mediated hemolytic gene <i>hlb</i> and staphyloxanthin-related <i>crtM</i>, <i>crtN</i> and <i>sigB</i> genes by quantitative polymerase chain reaction (qPCR). Meanwhile, the expression of oxidative stress-related genes <i>sodA</i>, <i>sodM</i> and <i>katA</i> also decreased. <i>Galleria Mellonella</i> assay revealed that SYG-180-2-2 was not toxic to larvae. Further, the larvae infection model showed that the virulence of bacteria was significantly reduced after 4 μg/mL SYG-180-2-2 treatment. SYG-180-2-2 also reduced skin abscess formation in mice by reducing bacterial burden and subcutaneous inflammation. In conclusion, SYG-180-2-2 might be a promising agent to attenuate the virulence of <i>S. aureus</i> by targeting genes associated with hemolytic activity and staphyloxanthin synthesis.