Methicillin-resistant Staphylococcus aureus (MRSA) infections account for a sanitary emergency in the clinic. Sepsis induced by MRSA leads to a marked aggressiveness of the infection, associated with a "cytokine-storm" that can is responsible for higher mortality due to multi-organ failure.
The discovery of new antibiotics, with immunomodulatory functions associated to an efficient antibacterial profile, is ideal to develop new therapies for MRSA-induced sepsis. Cannabis sativa-derived cannabinoids showed an intriguing antibacterial activity and, particularly, a significant killing activity against gram positive bacteria, including MRSA. Among different phytocannabinoids, cannabidiol (CBD) exerts a wide range of antioxidant, antinflammatory and immunoregulatory functions, including NO downregulation and iNOS protein expression inhibition in different experimental conditions and, in particular, during LPS-induced intestinal inflammation. Such activity is coupled to a safe profile in humans, whereas CBD lacks any psychotropic activity. In the attempt to increase CBD antibacterial activiy and pharmacokinetic potential, we will develop a series of CBD-related synthetic analogues (CBDrsa), by chemical elongation of pentyl chain of the CBD naïve molecule, and we will maximize drug permeabilization through the targeted bacteria and hosting tissues, through the encapsulation of both CBD and CBDrsa in niosomes or nanogels. We will explore the antimicrobial efficacy of CBD and CBDrsa, as nude molecules or vehicle-carried by niosomal and nanogel formulations, on reference strains of S. aureus/S. epidermidis spp and clinical MRSA isolates.
Since CBD is already available in the clinic as antiepileptic drug in Dravet syndrome, depending upon the successful results obtained by this research project, we will perform in vivo studies to propose the repositioning of this molecule or its derivatives as new class of antibiotic.
There is an urgent need for discovery and characterization of new antibiotic drugs. This requires a big economic effort and a complex network setup of different expertise synergizing in the attempt to develop a complete experimental approach ranging from pharmacological identification, pharmaceutical chemistry synthetic optimization and drug delivery approach, converging to maximize bacterial targeting and killing with negligible side effects. For this reason, to develope this project will be fundamental as starting point for a fast, bench to clinic transposition of a CBD as a very promising molecule, virtually nontoxic, widely characterized and already approved in clinics for Dravet Syndrome therapy. This research could also be considered as a starting point for the possible repositioning of CBD and the study of new CBD derivatives.
Moreover, the use of nanoparticulate systems is the ultimate frontier of drug delivery to effectively and efficiently deliver a drug to an action site. The objectives to be pursued with the inclusion of a drug in an appropriate nanocarrier are: maximizing the effectiveness of the drug itself, conveying it directly to the site of action and minimizing the side effects, reducing the drug distribution in the districts of organism not affected by the specific pathology. The mechanisms that make these systems interesting reside in the possibility of being appropriately engineered so as to exploit the various physiological mechanisms in order to release the drug directly to the site of interest.
In this particular case, niosomes and polymer-based nanohydrogels will be used and formulated with CBD and CBD derivatives in order to offer a double innovative approach for the treatment of infectious diseases caused by methicillin-resistant gram-positive bacteria.