Design, synthesis, and biological evaluation of membrane-active cannabichromene derivatives as potent antibacterial agents.

The increasing prevalence of multidrug-resistant (MDR) bacterial infections underscores the urgent need for novel antimicrobial agents with distinct mechanisms. In this study, we present the rational design and synthesis of cationic amphiphilic cannabichromene (CBC, 1) derivatives that mimic antimicrobial peptides (AMPs). Structural optimization of CBC through the incorporation of quaternary ammonium cations improved hydrophilicity and expanded the antibacterial spectrum. Among the 35 derivatives, compound 11F emerged as the lead candidate, exhibiting potent activity against Gram-positive (MIC = 0.25-0.5 μg/mL) and Gram-negative pathogens (MIC = 0.5-8 μg/mL), surpassing vancomycin and ceftazidime in efficacy. Mechanistic studies revealed that 11F disrupts bacterial membranes through high-affinity binding to phosphatidylglycerol (PG), resulting in membrane permeabilization and cytoplasmic leakage. Molecular dynamics simulations supported its membrane-targeting mechanism, driven by amphiphilic insertion into lipid bilayers. The synergistic accumulation of reactive oxygen species (ROS) further amplified the bactericidal effects. Compound 11F demonstrated low hemolysis and cytotoxicity, showing in vivo efficacy in a murine MRSA sepsis model (98.8 % bacterial reduction at 10 mg/kg) and displaying excellent safety. This study establishes compound 11F as a promising membrane-active antibacterial agent with potential for translation into clinical use against MDR infections.