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

Abstract

Candida albicans is an opportunistic fungal pathogen and most prevalent species among clinical outbreaks. It causes a range of infections, including from mild mucosal infections to serious life-threatening candidemia and disseminated candidiasis. Multiple virulence factors account for the pathogenic nature of C. albicans, and its morphological transition from budding yeast to hyphal form and subsequent biofilm formation is regarded as the most important reason for the severity of Candida infections. To address the demanding need for novel antifungals, we investigated the anti-biofilm activities of various methylindoles against C. albicans using a crystal violet assay, and the metabolic activity was assessed by using a 2,3-bis (2-methoxy-4-nitro-5-sulfo-phenyl)-2H-tetrazolium-5-carboxanilide reduction assay. Changes in biofilm morphologies and thicknesses were determined by confocal laser scanning microscopy and scanning electron microscopy, respectively. Of the 21 methylindoles tested, 1-methylindole-2-carboxylic acid (1MI2CA) at 0.1 mM (17.5 μg ml-1) and 5-methylindole-2-carboxylic acid (5MI2CA) at 0.1 mM effectively inhibited biofilm formation by C. albicans DAY185 and ATCC10231 strains. Moreover, 1MI2CA and 5MI2CA both effectively inhibited hyphal formation, and thus, improved C. albicans infected nematode survival without inducing acute toxic effects. Furthermore, our in silico molecular modeling findings were in-line with in vitro observations. This study provides information useful for the development of novel strategies targeting candidiasis and biofilm-related infections.

Mechanisms of action of antimicrobial peptides ToAP2 and NDBP-5.7 against Candida albicans planktonic and biofilm cells

“…Our results indicate that ToAP2 presented inhibitory action on both phases of biofilm formation. Amphotericin B but not fluconazole was also active in our tests, as previously reported 63,[76][77][78][79] .…”

Antibiofilm and Antivirulence Properties of Indoles Against Serratia marcescens

“…In our previous studies, we demonstrated the antibiofilm activities of indole derivatives, such as 7-hydroxyindole (Lee et al, 2009), 3-indoleacetonitrile, indole-3-carboxyaldehyde (Lee et al, 2011), 7-fluoroindole (Lee et al, 2012), 5-iodoindole (Lee et al, 2016), and methylindoles (Lee et al, 2018). In the current study, indole derivatives such as 5-fluoroxindole, 3-indoleacetonitrile, 5-fluoroindole, 6-fluoroindole, 7methylindole, 7-nitroindole, 5-chloro-2-methylindole, 7-methylindole-3-carboxaldehyde, 5-methylindole, indole-3-acetamide, indole-3-propionic acid, 4-benzyloxyindole and 5-benzyloxyindole inhibited biofilm formation by S. marcescens by 40-75% ( Figures 1B,E,H and Supplementary Figure 3).…”

“…Indole is an important bacterial signal molecule that regulates several important biological processes such as genetic stability, metabolism, biofilm formation, pathogenesis, antibiotic resistance, and oxidative stress responses and also acts as an interspecies and interkingdom signal to regulate diverse functions (Lee et al, 2015b). Several studies have described the antibiofilm and antivirulence activities of indole derivatives (e.g., 7-hydroxyindole, 3-indoleacetonitrile, 7-fluoroindole, 7benzyloxyindole, and methylindoles) against clinically important pathogens, such as enterohemorrhagic Escherichia coli (Lee et al, 2007), Pseudomonas aeruginosa (Lee et al, 2009(Lee et al, , 2011(Lee et al, , 2012, Staphylococcus aureus (Lee et al, 2013), and Candida albicans (Lee et al, 2018;Manoharan et al, 2018). In addition, indole and 3-indolylacetonitrile have been shown to inhibit the maturation of Paenibacillus alvei endospores (Kim Y.-G.et al, 2011), and halogenated indoles have been reported to have nematicidal and insecticidal potentials (Rajasekharan et al, 2019(Rajasekharan et al, , 2020.…”

Advances in Fungal Peptide Vaccines

“…Candida species are the most frequently isolated fungal species in blood cultures worldwide and these opportunistic pathogens cause a wide range of infections. Disseminated bloodstream infection has an estimated mortality rate of 40-60% even with the use of antifungal drugs [122][123][124][125]. Additionally, Candida commonly cause vaginitis, oral thrush, and infections of the skin and nails.…”