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

• Published in: European journal of medicinal chemistry Vol. 274; pp. 116544 - 116559
• Main Authors: Zhong, Rongcui, Xu, Zikai, Zhang, Shujun, Zeng, Minghui, Li, Haizhou, Liu, Shouping, Lin, Shuimu
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.08.2024; Elsevier
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Benzhydryl Compounds - chemical synthesis; Benzhydryl Compounds - chemistry; Benzhydryl Compounds - pharmacology; Bisphenol; Broad-spectrum; Cell Membrane - drug effects; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Development; Drug resistance; Gram-Positive Bacteria - drug effects; Hemolysis - drug effects; Humans; Life Sciences & Biomedicine; Membrane-targeting; Mice; Microbial Sensitivity Tests; Molecular Structure; Pharmacology & Pharmacy; Phenols - chemical synthesis; Phenols - chemistry; Phenols - pharmacology; Science & Technology; Structure-Activity Relationship; Membrane-targeting; Drug resistance; Broad-spectrum; Antibacterial agents; Bisphenol; RESISTANT; VANCOMYCIN
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116544

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.