Development of Membrane-Targeting Cannabigerol Derivatives as Potent Broad-Spectrum Antibacterial Agents
Abstract
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…
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