Abstract
Antimicrobial resistance threatens the viability of modern medicine, which is largely dependent on the successful prevention and treatment of bacterial infections. Unfortunately, there are few new therapeutics in the clinical pipeline, particularly for Gram-negative bacteria. We now present a detailed evaluation of the antimicrobial activity of cannabidiol, the main non-psychoactive component of cannabis. We confirm previous reports of Gram-positive activity and expand the breadth of pathogens tested, including highly resistant Staphylococcus aureus, Streptococcus pneumoniae, and Clostridioides difficile. Our results demonstrate that cannabidiol has excellent activity against biofilms, little propensity to induce resistance, and topical in vivo efficacy. Multiple mode-of-action studies point to membrane disruption as cannabidiol’s primary mechanism. More importantly, we now report for the first time that cannabidiol can selectively kill a subset of Gram-negative bacteria that includes the ‘urgent threat’ pathogen Neisseria gonorrhoeae. Structure-activity relationship studies demonstrate the potential to advance cannabidiol analogs as a much-needed new class of antibiotics.
Highlights
Antimicrobial resistance threatens the viability of modern medicine, which is largely dependent on the successful prevention and treatment of bacterial infections
In this study we have discovered that CBD and other cannabinoids have selective activity against a subset of Gram-negative bacteria that includes the Centers for Disease Control and Prevention (CDC) urgent priority and World Health Organisation (WHO) high priority drug-resistant pathogen N. gonorrhoeae
This bacteria causes infections that are increasingly unresponsive to existing antibiotics
Summary
The MIC90 against 132 MRSA and methicillin-susceptible S. aureus (MSSA) ATCC strains and Australian clinical isolates was 4 μg mL−1 (compared to 2 μg mL−1 for vancomycin, 4 μg mL−1 for daptomycin, and 64 μg mL−1 for clindamycin) (Fig. 1b, Supplementary Table 2). We initiated a medicinal chemistry campaign to attempt to improve the properties of CBD so that it can be used systemically to treat infections, with a focus on reducing protein binding/serum reversal while retaining or improving antibacterial activity We have tested both naturally occurring cannabinoids along with synthetic analogs designed to examine the importance of key structural features a Macromolecular synthesis: S. aureus. The methyl amide 5 was more active than the acid parent 4 against MRSA (16 vs. >64 μg mL−1) but slightly less active for N. gonorrhoeae (2–4 vs. 0.5–2 μg mL−1)
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