Discovery of novel cannabidiol derivatives with augmented antibacterial agents against methicillin-resistant Staphylococcus aureus

Drug-resistant bacterium infections are a severe threat to public health and novel antimicrobial agents combating drug-resistant bacteria are an unmet medical need. Although cannabidiol (CBD) has been reported to show antibacterial effects, whether its antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) can be improved remains unclear. Herein, a series of novel CBD derivatives were designed and synthesized using various chemical approaches including amidation, Friedel-Crafts alkylation, and Negishi cross-coupling reaction for the modifications at the C-7, C-2 ', C-4 ', and C-6 ' positions of CBD skeleton. Derivative 21f showed augmented antibacterial activity against MRSA with a minimum inhibitory concentration of 4 mu M without cytotoxic effect in microglia BV2 cells. Further mechanistic studies suggested that 21f inhibited the formation of biofilms, induced excess reactive oxygen species, and reduced bacterial metabolism, which collectively led to the acceleration of bacterial death. Findings from this study expand the understanding of CBD derivatives as promising antibacterial agents, which provides useful information for the development of cannabinoid-based antibacterial agents.

Automated summary

This study designed and synthesized a series of novel CBD derivatives, among which derivative 21f showed enhanced antibacterial activity against MRSA without cytotoxic effect. Mechanistic studies further revealed that 21f inhibited biofilm formation, induced reactive oxygen species, and reduced bacterial metabolism, leading to accelerated bacterial death.