Design, synthesis, and biological evaluation of tetrahydroquinoline amphiphiles as membrane-targeting antimicrobials against pathogenic bacteria and fungi

The rising prevalence of drug-resistant pathogens is one of the biggest threats to human health. The development of new antibiotics that can overcome drug resistance is in urgent need. Herein, we designed and synthesized a series of amphiphilic tetrahydroquinoline derivatives as small-molecule-based antimicrobial peptidomimetics. Two lead compounds 36 and 52 which contained the tetrahydroquinoline core, hydrophobic alkyl chains (n-nonyl or isoprenyl group), different spacer lengths (n = 4 or 8), and cationic guanidine moiety, showed poor hemolytic activity, low cytotoxicity, and potent broad-spectrum antimicrobial activity against Gram-positive and Gram-negative bacteria, as well as fungi. The further biological evaluation revealed that compounds 36 and 52 can kill bacteria and fungi rapidly via membrane-targeting action and avoid drug resistance development. More importantly, compounds 36 and 52 exhibited similarly potent in vivo antimicrobial activities in a murine corneal infection caused by Staphylococcus aureus ATCC29213 or Pseudomonas aeruginosa ATCC9027, as compared to vancomycin or gatifloxacin. These results suggest that compounds 36 and 52 have great potential as new broad-spectrum antimicrobial agents to combat microbial resistance. [Display omitted] •A series of tetrahydroquinoline amphiphiles as antimicrobials were synthesized by biomimicking AMPs.•The lead compounds 36 and 52 exhibited potent broad-spectrum antimicrobial activity, and low cytotoxicity.•36 and 52 can rapidly kill bacteria and fungi via membrane-targeting action and avoid drug resistance development.•36 and 52 exhibited potent in vivo antimicrobial activities in a murine corneal infection model.