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已发表论文
靶向细胞膜的大麻萜酚衍生物作为强效广谱抗菌剂的开发
Authors Yin Z, Zhang T, Wang Y, Wang Y, Xie X, Zhang F, Wang C , Hu W
Received 5 August 2025
Accepted for publication 7 January 2026
Published 23 January 2026 Volume 2026:20 558606
DOI https://doi.org/10.2147/DDDT.S558606
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Leonidas D. Panos
Zhicheng Yin, Tingting Zhang, Yipeng Wang, Yan Wang, Xiaoqing Xie, Fengyu Zhang, Chuandong Wang, Wei Hu
State Key Laboratory of Microbial Technology, Microbial Technology Institute, Shandong University, Qingdao, People’s Republic of China
Correspondence: Wei Hu, State Key Laboratory of Microbial Technology, Microbial Technology Institute, Shandong University, Qingdao, People’s Republic of China, Email hw_1@sdu.edu.cn Chuandong Wang, State Key Laboratory of Microbial Technology, Microbial Technology Institute, Shandong University, Qingdao, People’s Republic of China, Email wangchuandong@sdu.edu.cn
Purpose: This research aimed to develop novel membrane-targeting antibacterial agents via rational design and synthesis of hybrid compounds derived from cannabigerol (CBG) and antimicrobial peptide (AMP) motifs. This approach targeted key limitations of CBG, specifically its poor aqueous solubility, restricted activity against Gram-negative pathogens, and low bioavailability. By incorporating AMP domains, we intended to exploit their membrane-disruptive capability, thereby achieving enhanced broad-spectrum activity, diminished propensity for resistance, and improved pharmacological properties.
Methods: A library of membrane-active cannabigerol derivatives was designed and synthesized through conjugation of antimicrobial peptides structural motifs to the cannabigerol core scaffold by a flexible chemical linker. All compounds were characterized by 1H, 13C NMR, and high-resolution mass spectrometry. Antibacterial activity was evaluated using a broth microdilution method. Hemolytic activity was assessed against sheep erythrocytes, and cytotoxicity was determined using human cell lines. Mechanistic studies included molecular dynamics simulations, scanning electron microscopy, membrane depolarization and permeabilization assays, and quantification of reactive oxygen species generation. In vivo efficacy was validated in a murine peritonitis-sepsis model.
Results: The compound 5d demonstrated potent broad-spectrum activity against both Gram-positive and Gram-negative bacteria with low hemolytic toxicity and negligible cytotoxicity. Moreover, 5d exhibited rapid bactericidal action, resistance development prevention, and robust antibiofilm efficacy. Molecular dynamics simulations revealed the selective affinity of 5d for bacterial membranes. Mechanistic studies indicated membrane disruption via specific binding to phosphatidylglycerol and cardiolipin, leading to reactive oxygen species accumulation, DNA/proteins leakage, and bacterial death. In a murine peritonitis-sepsis model, 5d achieved superior survival rates and bacterial clearance compared to vancomycin.
Conclusion: Compound 5d demonstrated potent broad-spectrum antibacterial activity, an advantageous safety margin, and a low resistance propensity. Its membrane-disruptive mode of action underpins both efficacy and the reduced potential for resistance development. These attributes identify 5d as a promising lead for novel membrane-targeted anti-infective agents.
Keywords: cannabigerol derivatives, antimicrobial peptide, broad-spectrum antimicrobials, drug-resistant, membrane-targeting mode
State Key Laboratory of Microbial Technology, Microbial Technology Institute, Shandong University, Qingdao, People’s Republic of China
Correspondence: Wei Hu, State Key Laboratory of Microbial Technology, Microbial Technology Institute, Shandong University, Qingdao, People’s Republic of China, Email hw_1@sdu.edu.cn Chuandong Wang, State Key Laboratory of Microbial Technology, Microbial Technology Institute, Shandong University, Qingdao, People’s Republic of China, Email wangchuandong@sdu.edu.cn
Purpose: This research aimed to develop novel membrane-targeting antibacterial agents via rational design and synthesis of hybrid compounds derived from cannabigerol (CBG) and antimicrobial peptide (AMP) motifs. This approach targeted key limitations of CBG, specifically its poor aqueous solubility, restricted activity against Gram-negative pathogens, and low bioavailability. By incorporating AMP domains, we intended to exploit their membrane-disruptive capability, thereby achieving enhanced broad-spectrum activity, diminished propensity for resistance, and improved pharmacological properties.
Methods: A library of membrane-active cannabigerol derivatives was designed and synthesized through conjugation of antimicrobial peptides structural motifs to the cannabigerol core scaffold by a flexible chemical linker. All compounds were characterized by 1H, 13C NMR, and high-resolution mass spectrometry. Antibacterial activity was evaluated using a broth microdilution method. Hemolytic activity was assessed against sheep erythrocytes, and cytotoxicity was determined using human cell lines. Mechanistic studies included molecular dynamics simulations, scanning electron microscopy, membrane depolarization and permeabilization assays, and quantification of reactive oxygen species generation. In vivo efficacy was validated in a murine peritonitis-sepsis model.
Results: The compound 5d demonstrated potent broad-spectrum activity against both Gram-positive and Gram-negative bacteria with low hemolytic toxicity and negligible cytotoxicity. Moreover, 5d exhibited rapid bactericidal action, resistance development prevention, and robust antibiofilm efficacy. Molecular dynamics simulations revealed the selective affinity of 5d for bacterial membranes. Mechanistic studies indicated membrane disruption via specific binding to phosphatidylglycerol and cardiolipin, leading to reactive oxygen species accumulation, DNA/proteins leakage, and bacterial death. In a murine peritonitis-sepsis model, 5d achieved superior survival rates and bacterial clearance compared to vancomycin.
Conclusion: Compound 5d demonstrated potent broad-spectrum antibacterial activity, an advantageous safety margin, and a low resistance propensity. Its membrane-disruptive mode of action underpins both efficacy and the reduced potential for resistance development. These attributes identify 5d as a promising lead for novel membrane-targeted anti-infective agents.
Keywords: cannabigerol derivatives, antimicrobial peptide, broad-spectrum antimicrobials, drug-resistant, membrane-targeting mode