The antimicrobial potential of adarotene derivatives against Staphylococcus aureus strains.

[Display omitted] • Adarotene analogues were synthesized and investigated as antimicrobials. • The compounds exhibited activity against S. aureus strains, including resistant ones. • MD simulations on a lipid bilayer membrane systems of S. aureus were run. • A selected candidate showed tolerability on human cell lines and good PK profile. • An enhancement of the growth-inhibitory effect of rifaximin was demonstrated. Multidrug-resistant (MDR) pathogens are severely impacting our ability to successfully treat common infections. Here we report the synthesis of a panel of adarotene-related retinoids showing potent antimicrobial activity on Staphylococcus aureus strains (including multidrug-resistant ones). Fluorescence and molecular dynamic studies confirmed that the adarotene analogues were able to induce conformational changes and disfunctions to the cell membrane, perturbing the permeability of the phospholipid bilayer. Since the major obstacle for developing retinoids is their potential cytotoxicity, a selected candidate was further investigated to evaluate its activity on a panel of human cell lines. The compound was found to be well tolerated, with IC 50 5–15-fold higher than the MIC on S. aureus strains. Furthermore, the adarotene analogue had a good pharmacokinetic profile, reaching a plasma concentration of about 6 μM after 0.5 h after administration (150 mg/kg), at least twice the MIC observed against various bacterial strains. Moreover, it was demonstrated that the compound potentiated the growth-inhibitory effect of the poorly bioavailable rifaximin, when used in combination. Overall, the collected data pave the way for the development of synthetic retinoids as potential therapeutics for hard-to-treat infectious diseases caused by antibiotic-resistant Gram-positive pathogens. [ABSTRACT FROM AUTHOR]