Uncovering the hidden antibiotic potential of Cannabis

Abstract

26The spread of antimicrobial resistance continues to be a priority health concern worldwide, 27 necessitating exploration of alternative therapies. Cannabis sativa has long been known to contain 28 antibacterial cannabinoids, but their potential to address antibiotic resistance has only been 29 superficially investigated. Here, we show that cannabinoids exhibit antibacterial activity against 30 MRSA, inhibit its ability to form biofilms and eradicate stationary phase cells persistent to antibiotics. 31 We show that the mechanism of action of cannabigerol is through targeting the cytoplasmic membrane 32 of Gram-positive bacteria and demonstrate in vivo efficacy of cannabigerol in a murine systemic 33 infection model caused by MRSA. We also show that cannabinoids are effective against Gram-negative 34 organisms whose outer membrane is permeabilized, where cannabigerol acts on the inner membrane. 35Finally, we demonstrate that cannabinoids work in combination with polymyxin B against multi-drug 36 resistant Gram-negative pathogens, revealing the broad-spectrum therapeutic potential for Public Health agencies around the globe have identified antimicrobial resistance as one of the 62 most critical challenges of our time. The rapid and global spread of antimicrobial-resistant organisms in 63 recent years has been unprecedented. So much so that the world health organization (WHO) published 64 its first ever list of antibiotic-resistant "priority pathogens", made up of 12 families of bacteria that pose 65 the greatest threat to human health 1 . Among them, Staphylococcus aureus is the leading cause of both 66 healthcare and community-associated infections worldwide and a major cause for morbidity and 67 mortality 2 , especially with the emergence and rapid spread of methicillin-resistant S. aureus (MRSA), 68 which is resistant to all known β-lactam antibiotics 3 . Worse yet, resistance to vancomycin, linezolid 69 and daptomycin has already been reported in MRSA clinical strains, compromising the therapeutic 70 alternatives for life-threatening MRSA infections 4 . Further, antibiotic-resistant Gram-negative 71 infections have increasingly become a pressing issue in the clinic. Indeed, of the bacteria highlighted 72 by the WHO, 75% are Gram-negative organisms. Among the currently approved antibiotics, the latest 73 discovery of a new drug class dates back to more than 30 years ago. The rapid loss of antibiotic 74 effectiveness and diminishing pipeline beg for the exploration of alternative therapies. 75 Cannabis plants are important herbaceous species that have been used in folk medicine since 76 the dawn of times. Increasing scientific evidence is accumulating for the efficacy of its metabolites in 77 the treatment, for example, of epilepsy, Parkinson disease, analgesia, multiple sclerosis, Tourette's 78 syndrome and other neurological diseases 5 . At a very nascent stage are investigations into the potential 79 of cannabis metabolites as antibacterial therapies. To date, assessments of their antibacterial activ...

Cannabidiol (CBD) repurposing as antibacterial: promising therapy of CBD plus polymyxin B against superbugs

“…We observed antibacterial activity of ultrapure CBD against GP bacteria, M. tuberculosis, and LOS-expressing GND; but not against GNB, as recently described (17)(18)(19). Preliminary results regarding CBD activity in GP bacteria and its absence in GN bacteria (including MDR and XDR strains) were partially presented by us at ASM Microbe 2018 and published in the abstract book (15).…”

“…The CBD hydrophobic chemical structure may suggest the interaction of the molecule with lipid membranes, as described by Guard et al (2020) for eukaryotic cells, altering the biophysical properties of the membrane and affect the metabolism of lipids and cholesterol (11,25). The bacterial membrane was also suggested as a possible bacterial target for cannabinoids (cannabigerol [CBG] and CBD) (13,17,19). Also, Blaskovich et al (2021) also showed that CBD bactericidal concentrations against S. aureus lead to inhibition of protein synthesis, DNA, RNA, and peptidoglycan (19).…”

“…The absence of antibacterial activity of CBD against GNB may be related to LPS molecules and outer membrane proteins, from outer membrane, which would lead to the impermeability of macromolecules and limited diffusion of hydrophobic molecules, such as CBD (17)(18)(19). Our results of in vitro CBD antibacterial activity against GP bacteria and M.…”

“…The copyright holder for this preprint (which this version posted April 12, 2021. ; https://doi.org/10.1101/2021.04.12.439341 doi: bioRxiv preprint few studies described the antibacterial activity of ultrapure CBD against Gram-positive (GP) bacteria and its property of inhibiting biofilms formation and eradicate preformed biofilms (10,13,14,(17)(18)(19). In addition, few GNB species or genus as well as different phenotype/genotype of resistance have been evaluated, and the combination with antibiotics such as PB was poorly explored, particularly against MDR and XDR GNB, commonly called superbugs (20,21).…”

In Silico and In Vitro Analysis of Major Cannabis-Derived Compounds as Fatty Acid Amide Hydrolase Inhibitors

“…CBC shows antinociceptive and anti-inflammatory effects, and in vivo it potentiates some effects of THC [ 12 ]. CBG has antibacterial, antiproliferative, and bone-stimulant properties [ 13 , 14 , 15 ], whereas CBN is obtained by oxidation of THC in air and stimulates feeding in rats [ 16 ]. Finally, THCV has anorexic and antiepileptic effects, and it may be clinically effective to treat migraine [ 17 ].…”