Indole and 7-benzyloxyindole attenuate the virulence of Staphylococcus aureus

Abstract

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.

Efficacy of 7‐benzyloxyindole and other halogenated indoles to inhibit Candida albicans biofilm and hyphal formation

“…Consequently, we searched for new indole derivatives that inhibit biofilm formation rather than only cell growth to reduce the risk of drug‐resistance development. Previously, we have shown that 7‐benzyloxyindole had antivirulence activity and antibiofilm activity against persistent S. aureus infections in vitro (Lee et al ., 2013). In the present study, we studied benzyloxy and fluoro‐substituted indoles, and found that benzyloxy group is essential for antibiofilm activity against the fluconazole‐resistant Candida strain (Fig.…”

“…In Pseudomonas putida , signalling molecules such as indole enhances TtgGHI efflux pump that are relevant for antibiotic resistance (Molina‐Santiago et al ., 2014). The previous studies have reported that indole inhibits biofilm formation and suppresses the virulence of bacterial strains such as Staphylococcus aureus , Agrobacterium tumefaciens (Lee and Lee, 2010; Lee et al ., 2013, 2015a,b; Lee et al ., 2016) and Vibrio cholera (Mueller et al ., 2009). Likewise, indole derivatives such as 7‐fluoroindole, 7‐hydroxyindole, 3‐indolyl acetonitrile and 2‐aminobenzimidazoles have been reported to exhibit antimicrobial activities against pathogenic bacteria (Lee et al ., 2009, 2011, 2012, 2015a,b; Frei et al ., 2012).…”

Anti-biofilm, anti-hemolysis, and anti-virulence activities of black pepper, cananga, myrrh oils, and nerolidol against Staphylococcus aureus

“…Recently, we reported that a plant flavone (Lee et al 2012) and a bacterial signaling molecule indole (Lee et al 2013) reduced the production of staphyloxanthin and α-hemolysin.…”

Indole inhibits bacterial quorum sensing signal transmission by interfering with quorum sensing regulator folding

“…Highly expressed genes coding for proteases, molecular chaperones and TCA cycle enzymes in the presence of indole might play crucial roles in indole-induced stress conditions. Indole has been reported to act as an antivirulence compound against E. coli, Pseudomonas aeruginosa and Staphylococcus aureus (Lee et al, 2007(Lee et al, , 2009(Lee et al, , 2013Chu et al, 2012). Indole reduced virulence factors by modulating the expression of virulence and regulatory genes, which were reportedly regulated by the QS system in P. aeruginosa (Lee et al, 2009).…”