Figure 1.

Mechanism of action of ion channel blockers. (A) Chloroquine, ketoconazole, phenothiazines and verapamil inhibit eukaryotic efflux systems, allowing anti-TB drugs to achieve higher concentrations inside Mtb-infected host cells. Mtb promotes necrotic death of infected macrophages, leading to release of the bacteria into the extracellular space, where the bacteria continue to proliferate in the necrotic cells or infect new cells. In contrast, apoptotic cell death leads to enzymatic degradation of most of the bacteria. Dantrolene prevents necrotic death of Mtb-infected macrophages. (B) Phagocytosed Mtb (1) can also be eliminated through phagosome maturation and autophagy. In autophagy, isolation membranes (2) elongate and engulf phagosomes. The autophagosome-sequestered phagosomes (3) then fuse with lysosomes (4) to form autophagolysosomes (5), following which the lysosomal enzymes degrade the phagocytosed bacteria. Ambroxol, resveratrol, verapamil, fluoxetine, carbamazepine and valproic acid promote autophagy. In phagosome maturation, Mtb phagosomes fuse with lysosomes to form phagolysosomes (6). Phenothiazines promote acidification of phagolysosomes, thus enhancing activity of the lysosomal enzymes. In contrast, chloroquine inhibits phagosome maturation, thus preventing redox-induced Mtb drug tolerance, making the bacteria more susceptible to anti-TB drugs. (C) Phenothiazines and verapamil can also inhibit Mtb metabolism and efflux pump activity. Clofazimine, a second-line anti-TB agent, also inhibits Mtb metabolism. Created with BioRender.com.