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

Abstract

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.

Mode of action of the 2-phenylquinoline efflux inhibitor PQQ4R againstEscherichia coli

“…In a recent study, we showed that PQQ4R, when used at non-toxic concentrations, is also able to potentiate clarithromycin activity against intracellular M. avium in a manner similar to CPZ (Machado et al, 2015). On the contrary, PAβN showed almost no toxicity against the human macrophages, however, PAβN and its derivatives proved to be nephrotoxic as result of their accumulation in lysosomes.…”

“…In recent studies, the 2-phenylquinoline derivative PQQ4R showed to be active as an efflux pump inhibitor of the Gram-positive Staphylococcus aureus (Sabatini et al, 2011; Sabatini et al, 2013) and non-tuberculous mycobacteria (Machado et al, 2015) but nothing is known about its mode of action. In this work, we aimed to unravel the mode of action of PQQ4R as efflux pump inhibitor, as in the search for new and effective efflux inhibitors is important to understand their inhibitory mechanism of action and to disclosure the presence of non-efflux related mechanisms (Venter et al, 2015).…”

Pulmonary non-tuberculous mycobacterial infections: current state and future management

“…Commercial human gamma-globulin formulations have demonstrated prophylactic and therapeutic effect in challenge models with Mtb and BCG [306,307]. [315][316][317]319] • Polymorphism in the target gene (natural resistance to drugs-i.e. preventing drug binding)…”

“…• NTM can grow, survive and persist extra and intracellularly: o Escape macrophage apoptosis mechanism (possibility to spread and infect other cells) o Restriction of intra-phagosomal acidification o Decrease apoptosis and block autophagy flux [315,316,319,322] • Found within phagocytic cells and in granulomas in infected organs (lung and spleen)…”

Synthesis and mycobacterial evaluation of 5‐substituted‐6‐acetyl‐2‐amino‐7‐methyl‐5,8‐dihydropyrido‐[2,3‐d]pyrimidin‐4(3H)‐one derivatives

“…Bicyclic nitrogen heterocyclic scaffolds have been reported to possess efflux pump inhibition in various bacteria. 2‐Phenyl and 3‐phenylquinoline derivatives have been reported to be effective efflux pump inhibitors in nontuberculous mycobacteria, M. avium , and M. smegmatis . 2‐Phenylquinoline derivatives having a C‐6 benzyloxy group showed good inhibition of the S. aureus NorA pump .…”