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Home / Publications / Boosting Effect of 2-Phenylquinoline Efflux Inhibitors in Combination with Macrolides against Mycobacterium smegmatis and Mycobacterium avium

Boosting Effect of 2-Phenylquinoline Efflux Inhibitors in Combination with Macrolides against Mycobacterium smegmatis and Mycobacterium avium

  • Authors: Cannalire R, Cecchetti V, Couto I, Machado D, Manfroni G, Sabatini S, Santos Costa S, Tabarrini O, Viveiros M
  • Publication Year: 2015
  • Journal: ACS Infectious Diseases
  • Link: https://pubs.acs.org/doi/full/10.1021/acsinfecdis.5b00052

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.

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About GHTM

GHTM is a R&D Unit that brings together researchers with a track record in Tropical Medicine and International & Global Health. It aims at strengthening Portugal's role as a leading partner in the development and implementation of a global health research agenda. Our evidence-based interventions contribute to the promotion of equity in health and to improve the health of populations.

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