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

Abstract

SummaryCertain pathogenic bacteria and yeast form biofilms on biotic and abiotic surfaces including medical devices and implants. Hence, the development of antibiofilm coating materials becomes relevant. The virulence of those colonizing pathogens can be reduced by inhibiting biofilm formation rather than killing pathogens using excessive amounts of antimicrobials, which is touted as one of the main reasons for the development of drug resistance. Candida albicans is an opportunistic fungal pathogen, and the transition of yeast cells to hyphal cells is believed to be a crucial virulence factor. Previous studies have shown that indole and its derivatives possess antivirulence properties against various bacterial pathogens. In this study, we used various indole derivatives to investigate biofilm‐inhibiting activity against C. albicans. Our study revealed that 7‐benzyloxyindole, 4‐fluoroindole and 5‐iodoindole effectively inhibited biofilm formation compared to the antifungal agent fluconazole. Particularly, 7‐benzyloxyindole at 0.02 mM (4.5 μg ml−1) significantly reduced C. albicans biofilm formation, but had no effect on planktonic cells, and this finding was confirmed by a 2,3‐bis‐(2‐methoxy‐4‐nitro‐5‐sulfophenyl)‐2H‐tetrazolium‐5‐carboxanilide (XTT) assay and three‐dimensional confocal laser scanning microscopy. Scanning electron microscopy analyses revealed that 7‐benzyloxyindole effectively inhibited hyphal formation, which explains biofilm inhibition. Transcriptomic analysis showed that 7‐benzyloxyindole downregulated the expressions of several hypha/biofilm‐related genes (ALS3,ECE1,HWP1 and RBT1). A C. albicans‐infected Caenorhabditis elegans model system was used to confirm the antivirulence efficacy of 7‐benzyloxyindole.

Suppression of Fluconazole Resistant Candida albicans Biofilm Formation and Filamentation by Methylindole Derivatives

“…C. albicans biofilm infections are a serious problem for individuals with an implanted medical device, because they are resistant to the majority of clinical antifungal agents ( Silva et al, 2017 ). Some indole derivatives like indole-3-acetonitrile, tetracyclic indoles, and 7-benzyloxyindole have been reported for their antivirulence effects and drug resistance reversal potential against C. albicans ( Oh et al, 2012 ; Youngsaye et al, 2012 ; Manoharan et al, 2018 ), which prompted us to screen various commercially available methylindoles for their abilities to inhibit biofilm formation by fluconazole resistant C. albicans DAY185 (Figure 1 ). In the present investigation, we found two methylindoles, that is, 1MI2CA and 5MI2CA, significantly inhibited C. albicans DAY185 biofilm formation by >85% at 0.1 mM, which was 20-fold lower than its MIC for planktonic cells (Figure 2 ).…”

“…Several indoles and their derivatives have been reported to suppress the virulence and inhibit biofilm formation by several bacterial species, such as, Staphylococcus aureus, Agrobacterium tumefaciens, Pseudomonas aeruginosa ( Lee et al, 2009 , 2012 , 2013 , 2015 , 2016 ), and Vibrio cholera ( Mueller et al, 2009 ). Furthermore, some indole derivatives, such as, indole-3-acetonitrile, waikialoid A, shearinines, and 7-benzyloxyindole, have also been reported to inhibit C. albicans biofilm formation and hyphal development ( Oh et al, 2012 ; Wang et al, 2012 ; You et al, 2013 ; Manoharan et al, 2018 ). While several natural indole derivatives showed antibiofilm activity, but the number of active compounds is limited and methylindoles have not investigated yet.…”

Rapid Killing and Biofilm Inhibition of Multidrug-Resistant Acinetobacter baumannii Strains and Other Microbes by Iodoindoles

“…Indole acts as an interspecies and interkingdom signaling molecule and controls diverse bacterial functions [12,13]. Indole and its derivatives, such as 7-hydroxyindole [14], 3-indoleacetonitrile [15,16], 7-fluroindole [17], 2-aminobenzimidazoles [18], 7-benzyloxyindole [19,20] have been reported to attenuate the virulence of and biofilm formation by enterohemorrhagic E. coli O157:H7, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, Paenibacillus alvei, and Agrobacterium tumefaciens [21].…”

Interkingdom microbial consortia mechanisms to guide biotechnological applications

“…Biological recognition elements may serve as biosensors and universal signalling molecules, which can be manipulated to regulate microbial activities and to provide (semi-) quantitative analytical information, such as in bacterial/ fungal interactions, the human oral microbiome and the food industry (Kolenbrander et al, 2010;Bertels et al, 2012;Gao et al, 2016;Manoharan et al, 2018).…”