Synthesis and biological evaluation of indole-based peptidomimetics as antibacterial agents against Gram-positive bacteria

The emergence of bacterial multidrug resistance and the lack of new antimicrobial agents urgently demand the discovery and development of novel antibacterials that avoid bacterial resistance. Antimicrobial peptidomimetics represent a promising approach for overcoming antibiotic resistance. Herein we report the synthesis and evaluation of indole-based amphiphilic antimicrobial peptidomimetics, bearing hydrophobic side chains and hydrophilic cationic moieties. Among these derivatives, compound 28 demonstrated potent antimicrobial activity against Gram-positive bacteria, low hemolytic activity and low toxicity towards mammalian cells, as well as good stability in salt conditions. Moreover, compound 28 showed the rapid killing of bacteria via membrane-targeting action without developing bacterial resistance. More importantly, compound 28 displayed high antimicrobial potency against Gram-positive bacteria in a murine model of bacterial keratitis, and was found to be more efficient than vancomycin. Thus, compound 28 had great potential as a promising lead compound for the treatment of Gram-positive bacterial infection. [Display omitted] •Synthesis of cationic amphiphilic indole derivatives as membrane-active antimicrobial agents against Gram-positive bacteria.•The most promising compound 28 exhibited low hemolytic activity, high membrane selectivity, and excellent in vitro antibacterial activity against Gram-positive bacteria without inducing drug resistance.•Compound 28 displayed good stability under various salts, and low cytotoxicity towards mammalian cells.•Compound 28 exhibited high in vivo antimicrobial potency against Gram-positive bacteria.