## 1 Introduction
### Cannabinoids as Strategic Compounds to Develop New Antibiotics
Although the most studied cannabinoids for medicinal purposes are CBD and \(\Delta^{9}\)-THC, nowadays the research focus moves increasingly towards other PCs, such as the not psychoactive CBC, currently investigated for its anti-inflammatory, anti-fungal, antibiotic and analgesic effects [30], CBG and cannabigerolic acid (CBGA), which is the precursor of the decarboxylated CBG and could be considered as the \"mother of all cannabinoids\" (see later). Particularly, CBG has many putative benefits ranging from anti-inflammatory action to pain reliever [33]. Among other more investigated therapeutic properties, PCs including \(\Delta^{9}\)-THC, \(\Delta^{8}\)-THC, CBD, CBN, CBG, and CBC and some their correspondent carboxylic acids have shown from moderate to potent antimicrobial properties mainly against Gram-positive bacteria (MICs 0.5-8 ug/mL), and especially against strains of _S. aureus_, including MRSA, EMRSA, as well as fluoroquinoline and tetracycline-resistant strains, [34]. Particularly, even if the precise mechanisms used by PCs remains unknown so far, recent investigations have revealed that PCs inhibits bacteria by injuring their cytoplasmic membrane [35; 36]. Recently, [PERSON] et al. have reported the antibacterial activity of both CBD and CBG, being CBG the most potent compound, and their capability to inhibit _Staphylococci_ adherence to keratinocytes without compromising skin microbiota, thus being very promising as antibacterial agents to treat skin infection by topical administration [37]. [PERSON] et al., in addition to confirm the antibacterial activity of CBD on Gram-positive pathogens, including highly resistant _S. aureus_, _S. pneumoniae_, and _Clostridioides difficile_, demonstrated that CBD has excellent activity against biofilms, little propensity to induce resistance, and topical in vivo efficacy [38]. Moreover, the authors reported that CBD can selectively kill a subset of Gram-negative bacteria that includes the 'urgent threat' pathogen _Neisseria gonorrhoeaeae_[38]. Additionally, the interaction of CBD with broad-spectrum antibiotics such as ampicillin, kanamycin, and polymysxin B was studied by [PERSON] et al. [39]. By disrupting membrane integrity at extremely low dosages, CBD-antibiotic co-therapy showed synergistic activity against _Salmonella typhimurium_, offering an intriguing alternative in the treatment of this clinically relevant bacterium. The impressively strong antibacterial activity against MRSA of CBG has been reported by [PERSON] et al. in the year 2020 [33]. Even in comparison with standard therapy with vancomycin, CBG outcompetes classical approaches against MRSA. Additionally, CBG demonstrated to inhibit the capability of MRSA to generate de novo biofilm, showed to succeed in disaggregating the pre-formed biofilm, to kill rapidly stationary phase cells (persisters), and to effectively inhibit MRSA also in vivo, in a murine model. The authors speculated that C.  
sativa_ may produce PCs as a natural defense mechanism against pathogens and suggested PCs as a new compound class serving as novel antibiotic drug [33]. Unfortunately, since in _C. sativa_, CBGA is promptly and directly converted to CBDA and THCA, leaving no CBGA pool available to form CBG, the CBG levels in plants are exceptionally low. In this context, it has been suggested that a possible strategy to increase the CBG yield from hemp biomass could consist in harvesting much earlier in the ripening phase of the plants before the other cannabinoids are formed and detract the CBGA from the cannabinoid pool [40]. On the other hand, having available reliable synthetic procedures to prepare natural PCs would consent the accessibility to considerable quantities of CBG, as well as of other microbiologically promising minor cannabinoids, unlikely provided naturally by _Cannabis_ plants, thus allowing further studies finalized to the development of novel PCs-based antibiotics.