Exploring the Potential of Phytocannabinoids Against Multidrug-Resistant Bacteria

Abstract

The rapid emergence of multidrug-resistant (MDR) bacterial pathogens poses a critical threat to global health, creating an urgent need for novel antimicrobial agents. In this study, we evaluated a small library of natural and semisynthetic phytocannabinoids against a broad panel of MDR Gram-positive bacterial strains, evidencing very good activity in the low µM range. We provide evidence of the antibacterial activity of the two separated enantiomers of cannabidiol, offering novel insights into the stereochemical aspects of their bioactivity. To investigate the possible molecular targets and clarify the mechanism of action, we employed Inverse Virtual Screening (IVS), a computational approach optimized for predicting potential protein-ligand interactions, on three selected MDR bacterial species. Interestingly, key targets belonging to important bacterial metabolic pathways and defense mechanisms were retrieved, and the results were used to rationalize the observed biological activities. To the best of our knowledge, this study marks the first application of IVS to microorganisms, offering a novel strategy for identifying bacterial protein targets. The results pave the way for future experimental validation, structure-based drug design, and the development of novel antibacterial agents.

Keywords: antibacterial activity; cannabinoids; inverse virtual screening; multidrug resistance.

Figure 1

Chemical structures of the phytocannabinoids investigated.

Figure 2

The UniProt ID of the target that emerged from the normalization of the results of IVS on compounds 1–3.

Figure 3

Two-dimensional interaction diagram of compounds 1–5 with alcohol dehydrogenase YugJ. Pink arrows represent the hydrogen bonds, and the π-π stackings are represented by green lines. Polar residues are in cyan, hydrophobic ones are in green, and red or blue represent negatively and positively charged amino acids, respectively.