The identification of efflux inhibitors
to be used as adjuvants
alongside existing drug regimens could have a tremendous value in
the treatment of any mycobacterial infection. Here, we investigated
the ability of four 2-(4′-propoxyphenyl)quinoline Staphylococcus aureus NorA efflux inhibitors (<b>1</b>–<b>4</b>) to reduce the efflux activity in Mycobacterium smegmatis and Mycobacterium
avium strains. All four compounds were able to inhibit
efflux pumps in both mycobacterial species; in particular, <i>O</i>-ethylpiperazinyl derivative <b>2</b> showed an efflux
inhibitory activity comparable to that of verapamil, the most potent
mycobacterial efflux inhibitor reported to date, and was able to significantly
reduce the MIC values of macrolides against different <i>M. avium</i> strains. The contribution of the <i>M. avium</i> efflux
pumps MAV_1406 and MAV_1695 to clarithromycin resistance was proved
because they were found to be overexpressed in two <i>M. avium</i> 104 isogenic strains showing high-level clarithromycin resistance.
These results indicated a correlation between increased expression
of efflux pumps, increased efflux, macrolide resistance, and reduction
of resistance by efflux pump inhibitors such as compound <b>2</b>. Additionally, compound <b>2</b> showed synergistic activity
with clarithromycin, at a concentration below the cytotoxicity threshold,
in an ex vivo experiment against <i>M. avium</i> 104-infected
macrophages. In summary, the 2-(4′-propoxyphenyl)quinoline
scaffold is suitable to obtain compounds endowed with good efflux
pump inhibitory activity against both <i>S. aureus</i> and
nontuberculous mycobacteria
