ADMET Study and Inhibition of Staphylococcus Aureus Efflux Pumps by a Synthetic P-Aminochalcone

Bacterial resistance is a global health problem that needs to be solved through discovery of new therapeutic strategies. This study aimed to conduct in vitro assays to evaluate intrinsic and modulatory antimicrobial activity of (E)-1-(4-aminophenyl)-3-(4-ethoxyphenyl)prop-2-en-1-one (CPA-Etox) against different efflux pump producing Staphylococcus aureus strains, as well as to perform in silico studies to evaluate its pharmacokinetic properties (ADMET - absorption, distribution, metabolism, excretion, and toxicity) and to use molecular docking technique to identify molecular interactions between the aminochalcone with different efflux pumps (TetK, MepA, QacC, and QacA/B). Microbiological assays were performed using broth microdilution technique. CPA-Etox was tested alone or in combination with different antibacterial agents. CPA-Etox showed no direct antimicrobial activity but enhanced the antibacterial activity of norfloxacin against S. aureus K2068 (expressing mepA) and erythromycin against S. aureus RN-4220 (expressing msrA). CPA-Etox also increased the ethidium bromide activity against S. aureus K4100 (expressing qacC) and S. aureus K4414 (expressing qacA/B). Molecular docking showed the probable binding sites of CPA-Etox with the efflux pumps analyzed. Through in silico studies of pharmacokinetic properties, it was possible to observe that physical–chemical properties of CPA-Etox are within acceptable ADMET parameters, highlighting excellent correlation between the chalcone chemical structure and its pharmacokinetics, based on a high oral bioavailability and low toxicity response by ingestion. These results will be relevant for definition of possible CPA-Etox technological applications as an adjuvant to traditional antimicrobial agents in the treatment of staphylococcal infections caused by S. aureus strains expressing efflux pump genes.