RT Journal Article SR Electronic T1 Uncovering the hidden antibiotic potential of Cannabis JF bioRxiv FD Cold Spring Harbor Laboratory SP 833392 DO 10.1101/833392 A1 Maya A. Farha A1 Omar M. El-Halfawy A1 Robert T. Gale A1 Craig R. MacNair A1 Lindsey A. Carfrae A1 Xiong Zhang A1 Nicholas G. Jentsch A1 Jakob Magolan A1 Eric D. Brown YR 2019 UL http://biorxiv.org/content/early/2019/11/08/833392.abstract AB The spread of antimicrobial resistance continues to be a priority health concern worldwide, necessitating exploration of alternative therapies. Cannabis sativa has long been known to contain antibacterial cannabinoids, but their potential to address antibiotic resistance has only been superficially investigated. Here, we show that cannabinoids exhibit antibacterial activity against MRSA, inhibit its ability to form biofilms and eradicate stationary phase cells persistent to antibiotics. We show that the mechanism of action of cannabigerol is through targeting the cytoplasmic membrane of Gram-positive bacteria and demonstrate in vivo efficacy of cannabigerol in a murine systemic infection model caused by MRSA. We also show that cannabinoids are effective against Gram-negative organisms whose outer membrane is permeabilized, where cannabigerol acts on the inner membrane. Finally, we demonstrate that cannabinoids work in combination with polymyxin B against multi-drug resistant Gram-negative pathogens, revealing the broad-spectrum therapeutic potential for cannabinoids.