Research by a University of Southern Denmark team has found that the cannabis compound cannabidiol (CBD) may act as a helper compound to boost the effectiveness of antibiotics against drug-resistant Gram-positive bacteria. A study headed by Janne Kudsk Klitgaard, PhD, associate professor, clinical microbiology, found that combining CBD with the antibiotic bacitracin (BAC) had a more powerful effect against bacteria including Staphylococcus aureus, than BAC alone. “Based on these observations, the combination of CBD and BAC is suggested to be a putative novel treatment in clinical settings for treatment of infections with antibiotic-resistant Gram-positive bacteria,” the researchers stated in their published paper in Scientific Reports, titled, “Cannabidiol is an effective helper compound in combination with bacitracin to kill Gram-positive bacteria.”
Since the discovery of penicillin by Sir Alexander Fleming in 1928, antibiotics have saved millions of lives from fatal infections worldwide, the authors wrote. However, over time, bacteria have developed mechanisms to escape the effects of one or more antibiotics—multidrug resistance (MDR)—leading to an increasing global health threat. “With fewer antibiotics available to treat MDR bacterial infections, the possibility of entering a pre-antibiotic era is looming ahead,” the team stated.
Among alternative strategies that are being explored to help address antibiotic resistance, helper compounds, also known as antibiotic potentiators or resistant breakers, are gaining attention. Such helper compounds are non-antibiotic compounds that act as adjuvants for antibiotics, operating synergistically through mechanisms including efflux pump inhibition, enzyme inhibition, or changing membrane permeability, which can contribute to improving antibiotic efficacy.
Given that overuse of antibiotics is the main cause of antibiotic resistance, the combination of an antibiotic with a helper compound could reduce the amount of antibiotic needed to achieve bacterial growth inhibition or killing than if the antibiotic was used alone. “This strategy may, therefore, decrease the likelihood of resistance development, and investigations to identify efficient helper compounds are thus important,” the investigators suggested.
CBD, from the cannabis plant Cannabis sativa, acts as an antagonist of both the cannabinoid type 1 and 2 (CB1 and CB2) receptors, and has been shown to have anti-sedative, anti-psychotic, and anxiolytic effects, the team noted. The compound has also been linked with a variety of effects, including inhibiting cancer cell growth, neuroprotection in neurodegenerative diseases such as Parkinson’s disease, and post-ischemia, and anti-inflammatory effects, as in type 1 diabetes.
CBD has also been observed to inhibit bacterial growth, but the use of cannabidiol as an antibiotic adjuvant hasn’t yet been investigated, the team continued. “Not much is known regarding antimicrobial effects of cannabinoids and even less on the mechanism of action … the use of cannabidiol as an antibiotic adjuvant has not been studied so far.”
For their reported study, the researchers evaluated whether CBD could act as a potential helper compound to increase the effectiveness of the antibiotic bacitracin, which is a mixture of cyclic peptides that interfere with the bacterial cell wall and interrupt biosynthesis of peptidoglycan, leading to cell lysis. The team first validated the antimicrobial effect of cannabidiol against the Gram-positive bacteria methicillin-resistant Staphylococcus aureus (MRSA), and also against Enterococcus faecalis, Listeria monocytogenes, and methicillin-resistant Staphylococcus epidermidis (MRSE). They then tested the effects of combining CBD and BAC against different Gram-positive bacteria, providing initial indication that CBD could potentiate the antimicrobial effects of the antibiotic.
Further tests with the combination of CBD and BAC against S. aureus showed that dual treatment caused morphological changes in the bacterial cells that affected cell division, so that the bacteria could no longer divide normally. “… the combination of CBD and BAC affects the cell envelope causing irregular cell division visualized by multiple septa formations and irregular cell membrane.” These effects weren’t seen with either treatment on its own; “… CBD and BAC alone caused no morphological changes,” they wrote.
The combined treatment was also found to decrease autolysis in S. aureus, while CBD was shown to cause depolarization of the cytoplasmic membrane. Gene expression analysis confirmed that treatment using CBD in combination with BAC resulted in reduced expression of key cell division and autolysis genes in the bacteria. The combination of BAC and CBD was, however, and as expected, not effective in Gram-negative bacteria. As a mixture of cyclic peptides that interrupt cell wall synthesis in Gram-positive bacteria, the antibiotic is probably unable to cross the outer membrane in Gram-negative bacteria, the researchers pointed out.
“In this study, we found that the antibacterial effects of BAC against S. aureus as well as other Gram-positive bacteria can be enhanced by cannabidiol originating from the cannabis plant,” the scientists concluded. They acknowledged that further work will be needed to understand the mechanisms of action of combined CBD and BAC treatment on Gram-positive bacteria. “Changes observed in morphology were not caused by compositional changes in the cell wall muropeptide composition. Membrane potential changes for the combination of CBD and BAC compared to either CBD or BAC treatment alone did not reveal the mechanism of action for the combination of CBD and BAC,” they wrote. “Future studies are therefore focused on the cell division and cell envelope to identify the mechanism of action.”
