Halogenated indoles eradicate bacterial persister cells and biofilms

Abstract

The emergence of antibiotic resistance has necessitated new therapeutic approaches to combat recalcitrant bacterial infections. Persister cells, often found in biofilms, are metabolically dormant, and thus, are highly tolerant to all traditional antibiotics and represent a major drug resistance mechanism. In the present study, 36 diverse indole derivatives were investigated with the aim of identifying novel compounds that inhibit persisters and biofilm formation by Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus. 5-Iodoindole and other halogenated indoles, 4-fluoroindole, 7-chloroindole, and 7-bromoindole, eradicated persister formation by E. coli and S. aureus, and 5-iodoindole most potently inhibited biofilm formation by the two bacteria. Unlike other antibiotics, 5-iodoindole did not induce persister cell formation, and 5-iodoindole inhibited the production of the immune-evasive carotenoid staphyloxanthin in S. aureus; hence, 5-iodoindole diminished the production of virulence factors in this strain. These results demonstrate halogenated indoles are potentially useful for controlling bacterial antibiotic resistance.

Persistent Persister Misperceptions

“…Furthermore, substituted indoles reduce persistence (Lee et al, 2016). By testing 36 diverse indole derivatives for the ability to inhibit persister cells of Gram-negative E. coli and Gram-positive S. aureus , 5-iodoindole, 4-fluoroindole, 7-chloroindole, and 7-bromoindole were identified that eradicate persister cell formation by both bacteria.…”

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

“…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).…”

Interkingdom signal indole inhibits Pseudomonas aeruginosa persister cell waking

“…) and substituted indoles (Lee et al . ) have been shown to kill E. coli persister cells; however, they do not kill P. aeruginosa persisters (Lee et al . ).…”

“…) have been shown to kill E. coli persister cells; however, they do not kill P. aeruginosa persisters (Lee et al . ). Critically, the effect of indole on persister cell waking has not been investigated previously.…”

“…In regard to persister cells, indole (Hu et al 2015;Kwan et al 2015b) and substituted indoles (Lee et al 2016) have been shown to kill E. coli persister cells; however, they do not kill P. aeruginosa persisters (Lee et al 2016). Critically, the effect of indole on persister cell waking has not been investigated previously.…”