ADME/Tox study and the effect of β-Caryophyllene on the resistant strain of Staphylococcus aureus carrying the QacA/B efflux pump gene

The Gram-positive bacterium Staphylococcus aureus is responsible for causing both community-acquired and healthcare-associated infections, and it exhibits high antibiotic resistance due to the presence of efflux pumps. These pumps, such as QacA and QacB, are proteins that expel toxic substances, including antibiotics, making infection treatment more difficult. Among the alternatives to combat this resistance are terpenes, like β-caryophyllene, which have the potential to inhibit these efflux pumps due to their nonpolar nature. Considering this, the objective of this work is to investigate the ability of the mentioned terpene to act as an inhibitor of the QacA/B pump in S. aureus, as well as to analyze its pharmacokinetic and toxicological properties in silico. Initially, a molecular docking simulation was performed using the CryoEM structure of the QacA protein with the software AutoDock VINA to evaluate the interactions between β-caryophyllene and the target protein. Subsequently, in vitro assays were conducted to determine the Minimum Inhibitory Concentration (MIC) of β-caryophyllene and its ability to inhibit the efflux pump in combination with ampicillin in resistant strains of S. aureus. Additionally, in silico ADMET predictions were performed using the SwissADME platform. The results showed that the terpene enhanced the action of ampicillin, reducing the minimum inhibitory concentration (MIC) by 50 %. However, it was not able to reduce the MIC of ethidium bromide. The in silico analysis indicated that β-caryophyllene has good bioavailability and drug-likeness characteristics, but with limitations in its gastrointestinal absorption and brain permeability. The study concludes that β-caryophyllene is a promising candidate as an adjuvant in the treatment of antibiotic-resistant infections, especially due to its ability to partially inhibit efflux pumps.