Development of marine-derived indole derivatives as novel antibacterial agents against gram-positive bacteria

The escalating threat of bacterial infections, coupled with the diminishing efficacy of existing antibiotics, underscores an urgent demand for novel therapeutic strategy. Here, a total of eighteen indole derivatives inspired by the marine natural products and the amphipathic structure of cationic antimicrobial peptides were designed and synthesized. Among these compounds, 13e was identified as the most potent candidate, demonstrating potent activity against Gram-positive bacteria with minimum inhibitory concentrations ranging from 1 to 4 μg/mL, along with a promising selectivity index of 89.21. Furthermore, 13e exhibited rapid bactericidal effects, low propensity to induce resistance, excellent plasma stability, and effective biofilm inhibition and eradication. Mechanistic investigations revealed that 13e compromised bacterial membrane integrity by increasing permeability and depolarization, which induced the accumulation of endogenous reactive oxygen species and leakage of cytoplasmic proteins and nucleic acids, culminating in rapid bacterial cell death. More importantly, compound 13e exhibited potent in vivo antibacterial potency in a mouse subcutaneous infection model, making it a promising antimicrobial candidate to combat bacterial infection.