Indole derivative (um-3e) as an antimicrobial and antivirulence strategy for the prevention of staphylococcus aureus biofilm-associated infections

Intro: Antimicrobial resistance is a growing concern in recent years. Staphylococcus aureus infections remain a widespread nosocomial complication despite the use of prophylactic antibiotics and other preventive measures. The ability to form biofilms contribute to antibiotic/antimicrobial resistance, thus urging discovery of new antimicrobial compounds. The indole scaffold plays a prominent role in the field of drug design, attributing to its function as a chemical signalling molecule, bacterial metabolite and structural amenability. By altering substituent groups, a derivative targeting S. aureus antivirulence factors such as antibiofilm activities was fabricated. Methods: Antimicrobial susceptibility and antibiofilm activities of 45 indole derivatives were determined against methicillin-resistant (MRSA) and -sensitive (MSSA) S. aureus reference strains. The selected compound was subjected to confocal laser scanning microscopy analyses after staining with LIVE/DEAD® BacLightTM viability kit to determine reduction in biofilm thickness and volume. The inhibitory effects of the compound towards slime production and staphyloxanthin synthesis were evaluated. Cytotoxicity testing utilizing A549 human alveolar basal epithelial adenocarcinoma cells was performed. Findings: The compound labelled UM-3e had the lowest minimum biofilm inhibitory and eradication concentrations towards MSSA ATCC® 29213 (MBIC50: 3.13 μg/ml, MBEC50: 25 μg/ml) and MRSA ATCC® 33591 (MBIC50: 3.13 μg/ml, MBEC50: 3.13 μg/ml), respectively. MSSA biofilm biomass and thickness were reduced by ∼52% and ∼1.22 μm, respectively (p<0.05), while MRSA biofilm biomass was reduced by ∼73% (p<0.05) upon exposure to 3.13 μg/ml of UM-3e. Approximately 90% of staphyloxanthin biosynthesis was inhibited upon exposure to 3.13 μg/ml of UM-3e (p<0.05). S. aureus slime production was inhibited in the presence of 12.5 μg/ml of UM-3e. The compound did not significantly affect A549 cell viability at concentrations of up to 100 μg/ml. Conclusion: UM-3e was able to inhibit biofilm formation and eradicate S. aureus pre-formed biofilm, while exhibiting antivirulence properties including inhibition of slime and staphyloxanthin synthesis. The antibiofilm potential of this compound may serve as a milestone for development of virulence inhibitor antimicrobials that would be less likely to develop antibiotic resistance.