Combining Diclofenac and Cannabidiol to Enhance the Antibacterial Capacity of Nonantibiotic Drugs Through Potentiation

Antimicrobial resistance demands intensive research on new nonantibiotics and drug repurposing to expand the arsenal of antimicrobial agents. The present work analysed the combination of diclofenac (DFNAC) and cannabidiol (CBD) and evaluated its potentiation and its biocompatibility. The formulation’s potency has been tested against Staphylococcus epidermidis (S. epidermidis), Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), and P. aeruginosa. The DFNAC-CBD combination showed an evident synergistic effect, a significant decrease in the minimum inhibitory concentration against Staphylococcus epidermidis, and an additive effect against Staphylococcus aureus, indicating the levels of cooperation between the two compounds. All tested treatments exhibited MBC/MIC ratios ≤ 4, indicating bactericidal activity according to accepted interpretative criteria. Overall, the DFNAC-CBD combination accelerated bacterial killing relative to the individual compounds and exhibited a clear time-dependent antibacterial effect. The combination exhibited no antibacterial activity against Gram-negative strains such as E. coli and Pseudomonas aeruginosa. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Lactate Dehydrogenase (LDH) assays demonstrated that the antibacterial concentration (3.906 µg/mL) preserves cell viability and membrane integrity. Live/dead staining confirms cell viability and normal morphology. The results indicate that the DFNAC-CBD combination achieves antimicrobial efficacy through bactericidal rather than merely bacteriostatic activities and without inducing significant cytotoxicity. Therefore, the proposed DFNAC-CBD combination has significant potential as a nonantibiotic formula, which with further profile analysis can develop into formulations that can control the use and dosage of common antibiotics.