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 pre-formed biofilms and 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..

The exchange protein activated by cAMP (EPAC) is a promising drug target for a wide disease range, from neurodegeneration and infections to cancer and cardiovascular conditions. A novel partial agonist of the EPAC isoform 1 (EPAC1), I942, was recently discovered, but its mechanism of action remains poorly understood. Here, we utilize NMR spectroscopy to map the I942–EPAC1 interactions at atomic resolution and propose a mechanism for I942 partial agonism. We found that I942 interacts with the phosphate binding cassette (PBC) and base binding region (BBR) of EPAC1, similar to cyclic adenosine monophosphate (cAMP). These results not only reveal the molecular basis for the I942 vs cAMP mimicry and competition, but also suggest that the partial agonism of I942 arises from its ability to stabilize an inhibition-incompetent activation intermediate distinct from both active and inactive EPAC1 states. The mechanism of action of I942 may facilitate drug design for EPAC-related diseases.

HIV-1 integrase multimerization inhibitors have recently been established as an effective class of antiretroviral agents due to their potent ability to inhibit viral replication. Specifically, quinoline-based inhibitors have been shown to effectively impair HIV-1 replication, highlighting the importance of these heterocyclic scaffolds. Pursuant of our endeavors to further develop a library of quinoline-based candidates, we have implemented a structure−activity relationship study of trisubstituted 4-arylquinoline scaffolds that examined the integrase multimerization properties of substitution patterns at the 4position of the quinoline. Compounds consisting of substituted phenyl rings, heteroaromatics, or polycyclic moieties were examined utilizing an integrase aberrant multimerization in vitro assay. para-Chloro-4-phenylquinoline 11b and 2,3benzo[b][1,4]dioxine 15f showed noteworthy EC 50 values of 0.10 and 0.08 μM, respectively.

The synthesis of three phenolic natural products has been accomplished with unprecedented efficiency using a new alumina-promoted regioselective aromatic allylation reaction. Cannabigerol and grifolin were prepared in one step from the inexpensive 5-alkyl-resorcinols olivetol and orcinol. Piperogalin was synthesized, for the first time, via two sequential allylations of orcinol with geraniol and prenol.

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...