Development of novel bisphenol derivatives with a membrane-targeting mechanism as potent gram-positive antibacterial agents

Antibiotic resistance is becoming increasingly severe. The development of small molecular antimicrobial peptides is regarded as a promising design strategy for antibiotics. Here, a series of bisphenol derivatives with amphiphilic structures were designed and synthesized as antibacterial agents by imitating the design strategy of antimicrobial peptides. After a series of structural optimizations, lead compound 43 was identified, which exhibited excellent antibacterial activity against Gram-positive bacterial strains (MICs = 0.78–1.56 μg/mL), poor hemolytic activity (HC50 > 200 μg/mL), and low cytotoxicity (CC50 > 100 μg/mL). Further biological evaluation results indicated that 43 exerted antibacterial effects by directly destroying bacterial cell membranes and displayed rapid bactericidal properties (within 0.5–1 h), leading to a very low probability of drug resistance. Moreover, in a murine model of corneal infection, 43 exhibited a strong in vivo antibacterial efficacy. These findings indicate that 43 is a promising candidate compound for the treatment of bacterial infections. [Display omitted] •A series of bisphenol derivatives as antimicrobials were synthesized by imitating cationic antimicrobial peptides (CAMPs).•The lead compound 43 displayed excellent antibacterial activity, poor hemolytic activity, and low cytotoxicity in vitro.•Compound 43 exerted antibacterial effects by directly destroying bacterial cell membranes, leading to a low probability of drug resistance.•Compound 43 exhibited a strong in vivo antibacterial efficacy in a murine corneal infection model.