Infectious diseases have been associated with morbidity and mortality throughout the history of mankind. Antibiotics were considered the ultimate weapon against bacteria. However, over time, bacteria have developed mechanisms to overcome the killing effect of antibiotics. Moreover, the bacterial pathogens’ ability to adapt to and overcome the challenges of antibiotics has been dramatically enhanced of late. Not only are rates of bacterial resistance to individual drugs or drug classes a concern, but the prevalence of multidrug-resistant strains (resistant to three or more drug classes) is an even more serious therapeutic challenge1.

Some of the more problematic drug-resistant pathogens encountered today include methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Streptococcus pneumoniae, and vancomycin-resistant Enterococcus spp. among the gram-positive bacteria, and multidrug-resistant Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa among the gram-negative bacteria2.

A multidrug-resistant phenotype can arise in bacteria through the acquisition of multiple acquired resistance mechanisms due to environmental pressure. These resistance factors can stem from mobile genetic elements, a combination of acquired and chromosomally encoded resistance mechanisms, or accumulation of multiple chromosomal changes over time. Another means for bacteria to evolve resistance to antibiotics is a single or poly-mutational event leading to overexpression of a multidrug-resistance mechanism, i.e., an efflux pump, or genes encoding a specific drug-deactivating enzyme3.

S. aureus are not naturally pathogenic and commonly colonize human epithelia. However, infections can occur on epithelial surfaces, ranging from pimples and impetigo to pneumonia and meningitis4. Furthermore, pathogenicity can develop through infection of S. aureus in the bloodstream, and these infections are of great medical importance due to their prevalence and virulence5,6.

Infections caused by antibiotic-resistant strains of S. aureus have spread globally and reached epidemic proportions worldwide7. In addition to the increasing prevalence and incidence of community-associated methicillin-resistant S. aureus (CA-MRSA), the strains appear to be especially virulent8. Overwhelming and tissue-destructive infections, such as necrotizing fasciitis and fulminant, necrotizing pneumonia, have been associated with CA-MRSA strains9. Moreover, MRSA can colonize the health care units of hospitals and clinics10,11,12 and therefore are of specific public danger.

All implanted medical devices are susceptible to colonization by staphylococci and staphylococcal biofilm-associated infections, from indwelling catheters to prosthetic heart valves, cardiac pacemakers, contact lenses, cerebrospinal fluid shunts, joint replacements and intravascular lines13. Damaged host tissue is also a risk factor for developing biofilm-associated infection14.

Biofilms are highly structured surface-associated communities of microorganisms that are enclosed in a self-produced protective extracellular matrix15,16,17. Typically, these biofilms are associated with increased resistance to antimicrobial compounds17 and are generally less affected by host immune factors. Bacterial biofilms are known to cause more than 75% of microbial infections in humans18. Therefore, there is an urgent need for antibacterial agents that not only target multidrug-resistant pathogens, thereby decreasing the use of antibiotics and hence their side effects, but also eliminate biofilms. An important potential strategy to help combat the resistance problem involves the discovery and development of new active agents capable of partly or completely suppressing bacterial resistance mechanisms19.

The endocannabinoid system (ECS) is composed of endocannabinoids (ECs) and enzymes for their synthesis and degradation, as well as the cannabinoid receptors CB1 and CB2, which are widely distributed throughout the body. Cannabinoid receptors are activated by different ligands that are either endogenous, such as the ECs, or exogenous, such as delta-9-tetrahydrocannabinol (THC) present in Cannabis sativa and synthetic cannabinoid-like compounds20,21. The ECS has been shown to affect numerous physiological processes, including appetite, the immune response, sleep, bone density, and neuroprotection. The ECS is thought to be a neuromodulator22,23 and an immunomodulator24. Functionally, the activation of cannabinoid receptors has been shown to play a role in the activation of GTPases in macrophages and neutrophils. These receptors have also been implicated in the proper migration of B cells into the marginal zone and the regulation of healthy IgM levels25. The EC anandamide (AEA) and EC-like arachidonoyl serine (AraS) are endogenous constituents in mammals and some other animal species26,27. AEA binds to both cannabinoid receptors; AraS does not bind to the receptors, but its neuroprotective activity can be blocked by CB2 receptor antagonists, indicating that it is part of the ECS28.

There is limited information concerning the role of the ECS during infection, particularly against invading bacteria. A previous study showed antimicrobial effects of C. sativa extracts on different pathogens29. Another work demonstrated strong antibacterial activity of selected cannabinoids against MRSA strains, indicating the therapeutic potential of some cannabinoids for the treatment of antibiotic-resistant S. aureus30. We have previously shown that the potent synthetic cannabinoid receptor agonist HU-210 reduces biofilm formation in a strain of Vibrio harveyi31. As biofilm formation is one of the routes of bacterial resistance to antibiotics, we posited that EC and EC-like compounds may also show antibacterial/antibiofilm activity and may represent one of the body’s reactions to invasion of bacteria and to bacteria which are resistant to antibiotics.