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

Abstract Multidrug-resistant (MDR) and extensively drug-resistant (XDR) bacteria are a major worldwide public health problem. In the last decades, resistance to last-resort antibiotics such as polymyxin B (PB) have been increasingly observed among these superbugs, compromising the effectiveness of antimicrobial therapy. The present study aimed (i) to assess the ultrapure Cannabidiol (CBD) antibacterial activity against a broad diversity of Gram-negative (GN) and Gram-positive (GP) bacteria (44 different species, 95 strains), comprising standard strains and clinical isolates, and (ii) to investigate the antibacterial activity of the combination CBD + PB against GN bacteria, including chromosomal- and plasmid-acquired PB-resistant and intrinsically PB-resistant GNB. We evaluated CBD in vitro antibacterial activity using the standard broth microdilution method, and the antibacterial activity of the combination CBD + PB was screened using the standard broth microdilution and confirmed by checkerboard assay. CBD exhibited antibacterial activity against different GP bacterial species, lipooligosaccharide (LOS)-expressing GN diplococcus (GND) ( Neisseria gonorrhoeae , Neisseria meningitidis , and Moraxella catarrhalis ), and Mycobacterium tuberculosis . The combination CBD + PB exhibited antibacterial activity against PB-resistant GNB (e.g., Klebsiella pneumoniae ) as well as additive and/or synergistic effect against LOS-expressing GND. The antibacterial activity of the combination CBD + PB against Pseudomonas aeruginosa and plasmid-mediated colistin-resistant (MCR-1) E. coli strains could be only demonstrated in the presence of phenylalanine-arginine-β-naphthylamide (PAβN). In conclusion, our results show promising translational potential of the combination CBD + PB against MDR and XDR GNB, including PB-resistant K. pneumoniae , highlighting its potential as a rescue treatment for life-threatening infections caused by these superbugs. One Sentence Summary Promising combination of cannabidiol (CBD) + polymyxin B (PB) against superbugs (e.g., PB-resistant Gram-negative bacilli): Repurposing CBD ### Competing Interest Statement JAC is a member of the International Advisory Board of the Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE) National Health and Medical Research Council (NHMRC). JAC and JEH have received travel support to attend scientific meetings and personal consultation fees from BSPG-Pharm. JAC, JEH, and AWZ are coinventors of the patent Fluorinated CBD compounds, compositions and uses thereof. Pub. No.: WO/2014/108899. International Application No.: PCT/IL2014/050023, Def. US number Reg. 62193296; July 29, 2015; INPI on August 19, 2015 (BR1120150164927; Mechoulam R, Zuardi AW, Kapczinski F, Hallak JEC, Guimaraes FS, Crippa JAS, Breuer A). Universidade de Sao Paulo (USP) has licensed this patent to Phytecs Pharm (USP Resolution No. 15.1.130002.1.1) and has an agreement with Prati-Donaduzzi to develop a pharmaceutical product containing synthetic CBD and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinson s disease, and anxiety disorders. JAC, JEH, and AWZ are coinventors of the patent Cannabinoid-containing oral pharmaceutical composition, method for preparing and using same, INPI on September 16, 2016 (BR 112018005423-2). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The other authors declare that they have no conflicts of interest.