Adarotene-related retinoids as potential antimicrobial agents against multidrug-resistant gram-positive strains

Multidrug-resistant (MDR) pathogens are severely impacting our ability to successfully treat common infections. As a consequence, bacterial resistance to antimicrobial drugs represents one of the most impelling topics in medicinal chemistry. In recent years we have focused our efforts on the investigation of a panel of adarotene-related synthetic retinoids showing, together with favorable MICs, a detectable bactericidal effect on S. aureus and E. faecalis (including some MDR strains).¹ Based on these promising results, a small collection of adarotene related retinoids was prepared. Chemical modifications were performed on the carboxylic group and the double bond of the cinnamic portion, as well as polar substituents were introduced on ring A and ring B, in order to evaluate the potential structural determinants necessary to exert antibiotic activity (Figure 1). Overall, the results showed that compounds with a very good activity profile can be obtained by modulating the pattern of substitution on the adarotene moiety. Moreover, the shape and geometry of the molecules, together with the presence of key polar groups on the biphenyl backbone, could play a major role for the antimicrobial effect on resistant strains.

Figure 1: Structure of adarotene and suitable modifications on its scaffold.