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.

Antibacterial agents; Bisphenol; Broad-spectrum; Drug resistance; Membrane-targeting.