Human pathogens can readily develop drug resistance due to the long-term use of
antibiotics that mostly inhibit bacterial growth. Unlike
antibiotics, antivirulence compounds diminish bacterial virulence without affecting cell viability and thus, may not lead to drug resistance. Staphylococcus aureus is a major agent of
nosocomial infections and produces diverse
virulence factors, such as the yellow
carotenoid staphyloxanthin, which promotes resistance to
reactive oxygen species (ROS) and the host immune system. To identify novel antivirulence compounds, bacterial signal
indole present in animal gut and diverse
indole derivatives were investigated with respect to reducing
staphyloxanthin production and the hemolytic activity of S. aureus. Treatment with
indole or its derivative 7-benzyloxyindole (7BOI) caused S. aureus to become colorless and inhibited its hemolytic ability without affecting bacterial growth. As a result, S. aureus was more easily killed by
hydrogen peroxide (H₂O₂) and by human whole blood in the presence of
indole or 7BOI. In addition, 7BOI attenuated S. aureus virulence in an in vivo model of nematode Caenorhabditis elegans, which is readily infected and killed by S. aureus. Transcriptional analyses showed that both
indole and 7BOI repressed the expressions of several virulence genes such as α-
hemolysin gene hla,
enterotoxin seb, and the
protease genes splA and sspA and modulated the expressions of the important regulatory genes agrA and sarA. These findings show that
indole derivatives are potential candidates for use in antivirulence strategies against persistent S. aureus
infection.