**5. Conclusions**

Both phytocannabinoids and endocannabinoids have diverse physiological activities that are, in part, mediated by common receptors in mammalians, each compound with its specificity and affinity, being agonists, partly agonists, inverse agonists, or antagonists. While these mechanisms have been widely investigated, the mechanisms leading to their anti-microbial effects are less understood. Despite the quite different structures of phytocannabinoids and endocannabinoids (Figures 1 and 3), there are some common dominators that characterize their anti-bacterial activities (Figures 2 and 4). For instance, they exert bacteriostatic activity, alter the membrane structure, induce either membrane hyperpolarization or depolarization, modulate gene expression including those involved in metabolism, affect virulence factors, and prevent biofilm formation (Figures 2 and 4). Additionally, the AEA-mediated inhibition of yeast-hypha transition of *Candida albicans* and the hyphal adherence to epithelial cells seem to be mediated by alterations in gene expression (Figure 5). The multiple actions of phytocannabinoids and endocannabinoids sugges<sup>t</sup> that the compounds do much more than just affecting membrane permeability as previously thought.

The emergence of antibiotic-resistant microbes is a clinical problem worldwide, and novel treatment strategies are urged. The important observation that some of the phytocannabinoids and endocannabinoids act on both drug-sensitive and drug-resistant *Staphylococcus aureus* makes them potential antibiotic adjuvants in treating drug-resistant infections, for instance for topical infectious wound treatment. Especially important is the ability of AEA and AraS to sensitize drug-resistant *Staphylococcus aureus* to antibiotics in virtue of their ability to prevent drug efflux and induce growth arrest. The addition of these endocannabinoids to the treatment cocktail will revive the use of already existing antibiotics. The ability of both CBG and the synthetic cannabinoid HU-210 to antagonize quorum sensing may have implications in the new era where quorum sensing inhibitors or quorum quenchers have attracted attention for alternative antibiotic drugs for antibioticresistant bacteria [450]. To reach this goal, further studies should be performed to clarify the spectrum of bacteria whose quorum sensing pathways are affected by cannabinoids. The increasing recognition of the complex interplay between the gu<sup>t</sup> microbiota and the endocannabinoid system with the accompanying implications for various physiological and pathophysiological conditions, places the therapeutic uses of cannabinoids into a new spotlight.

**Author Contributions:** Conceptualization, R.V.S. and D.S.; writing—original draft preparation, R.V.S.; writing—review and editing, R.V.S. and D.S. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** The authors want to thank Goldie Wolfson for her English editing of the manuscript.

**Conflicts of Interest:** The authors declare no conflict of interest.
