Development of Highly Potent Carbazole Amphiphiles as Membrane-Targeting Antimicrobials for Treating Gram-Positive Bacterial Infections.

The development of new antimicrobial agents capable of curing drug-resistant bacteria-induced infections is becoming a major challenge to the global healthcare system. To develop antimicrobials with new molecular entities, a series of novel carbazole-based compounds were designed and synthesized by biomimicking the structural properties and biological function of antimicrobial peptides. Compound was selected as a lead compound from the structure-activity relationship analyses and biological activity evaluation. Compound showed excellent antimicrobial activity against Gram-positive bacteria (MICs = 0.78-1.56 μg/mL), poor hemolytic activity (HC > 200 μg/mL), and low cytotoxicity to mammalian cells. Compound had fast bactericidal properties and effectively prevented bacterial resistance in laboratory simulations. Antibacterial mechanism studies revealed that compound directly destroyed bacterial cell membranes, leading to bacterial deaths. Importantly, compound displayed an excellent efficacy in a murine bacterial keratitis model caused by ATCC29213.