AUTHOR=Rao Lulin , Xu Yanlei , Shen Li , Wang Xinyi , Zhao Huilin , Wang Bingjie , Zhang Jiao , Xiao Yanghua , Guo Yinjuan , Sheng Yaoguang , Cheng Lixia , Song Zengqiang , Yu Fangyou 

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

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2022.1008289

DOI=10.3389/fcimb.2022.1008289

ISSN=2235-2988

ABSTRACT=<p>Multi-drug resistant <italic>Staphylococcus aureus</italic> 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 (C<sub>21</sub>H<sub>16</sub>N<sub>2</sub>OSe), 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 <italic>Staphylococcus aureus</italic>. 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 <italic>S. aureus</italic>. Besides, SYG-180-2-2 strongly inhibited the hemolytic activity and staphyloxanthin synthesis in <italic>S. aureus</italic>. Inhibition of staphyloxanthin by SYG-180-2-2 enhanced the sensitivity of <italic>S. aureus</italic> to oxidants and human whole blood. In addition, SYG-180-2-2 significantly decreased the expression of <italic>saeR</italic>-mediated hemolytic gene <italic>hlb</italic> and staphyloxanthin-related <italic>crtM</italic>, <italic>crtN</italic> and <italic>sigB</italic> genes by quantitative polymerase chain reaction (qPCR). Meanwhile, the expression of oxidative stress-related genes <italic>sodA</italic>, <italic>sodM</italic> and <italic>katA</italic> also decreased. <italic>Galleria Mellonella</italic> 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 <italic>S. aureus</italic> by targeting genes associated with hemolytic activity and staphyloxanthin synthesis.</p>