Total Synthesis and Antibacterial Evaluation of (-)- and (+)-epi-Perrottetinene

Antimicrobial resistance (AMR) is a critical threat to global public health, with emerging resistance to Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), often referred to as a silent pandemic. Despite ongoing efforts in the fight against AMR, the drug discovery pipeline remains underdeveloped, highlighting the urgent need to explore natural and synthetic approaches. Cannabinoid-inspired natural products represent an underexplored chemical space with antimicrobial potential. Herein, we report an efficient, scalable, and enantioselective synthesis and antimicrobial evaluation of epi-perrottetinene (epi-PET), an unnatural bibenzyl-based cannabinoid analog of liverwort-derived perrottetinene. The synthetic strategy employs inexpensive starting materials and a Lewis acid-mediated Friedel-Crafts cyclization to enable regioselective access to both Δ8- and Δ9-epi-PET isomers. Biological evaluation revealed potent antibacterial activity against Gram-positive pathogens, with particularly strong efficacy against drug-sensitive and drug-resistant S. aureus strains, including MRSA clinical isolates. Notably, the lead compound E exhibited remarkable activity, with MIC values ≤ 1.2 μg/mL. Compound E remained effective against efflux pump-overexpressing strains and bacterial biofilms and eradicated intracellular bacteria, while displaying low hemolytic activity (3.4% of rabbit erythrocytes) and minimal cytotoxicity toward mammalian cell lines (N2a and RAW). Mechanistic studies indicate that bacterial membrane disruption is a key contributor to the observed bactericidal activity, consistent with rapid killing and a low propensity for resistance development. The work establishes epi-perrottetinene as a promising cannabinoid-inspired antibacterial scaffold and highlights the potential of nonclassical cannabinoids as a source of new chemical matter for addressing antimicrobial resistance.