Boosting Effect of 2-Phenylquinoline Efflux Inhibitors in Combination with Macrolides against Mycobacterium smegmatis and Mycobacterium avium.
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 (1-4) 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, O-ethylpiperazinyl derivative 2 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 M. avium strains. The contribution of the M. avium efflux pumps MAV_1406 and MAV_1695 to clarithromycin resistance was proved because they were found to be overexpressed in two M. avium 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 2. Additionally, compound 2 showed synergistic activity with clarithromycin, at a concentration below the cytotoxicity threshold, in an ex vivo experiment against M. avium 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 S. aureus and nontuberculous mycobacteria.
Grupo de Micobactérias, Unidade de Microbiologia Médica, Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa (IHMT, UNL) , Rua da Junqueira 100, 1349-008 Lisboa, Portugal.
Diana
D
Machado
Department of Pharmaceutical Sciences, Università degli Studi di Perugia , Via del Liceo 1, 06123 Perugia, Italy.
Rolando
R
Cannalire
Grupo de Micobactérias, Unidade de Microbiologia Médica, Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa (IHMT, UNL) , Rua da Junqueira 100, 1349-008 Lisboa, Portugal.
Sofia
S
Santos Costa
Department of Pharmaceutical Sciences, Università degli Studi di Perugia , Via del Liceo 1, 06123 Perugia, Italy.
Giuseppe
G
Manfroni
Department of Pharmaceutical Sciences, Università degli Studi di Perugia , Via del Liceo 1, 06123 Perugia, Italy.
Oriana
O
Tabarrini
Department of Pharmaceutical Sciences, Università degli Studi di Perugia , Via del Liceo 1, 06123 Perugia, Italy.
Violetta
V
Cecchetti
Grupo de Micobactérias, Unidade de Microbiologia Médica, Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa (IHMT, UNL) , Rua da Junqueira 100, 1349-008 Lisboa, Portugal.
Isabel
I
Couto
Grupo de Micobactérias, Unidade de Microbiologia Médica, Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa (IHMT, UNL) , Rua da Junqueira 100, 1349-008 Lisboa, Portugal.
Miguel
M
Viveiros
Department of Pharmaceutical Sciences, Università degli Studi di Perugia , Via del Liceo 1, 06123 Perugia, Italy.
Stefano
S
Sabatini
Mycobacterium avium complex; antimicrobial resistance; drug synergism; efflux pump; nontuberculous mycobacteria