Inhibition of tubercle bacilli in cultured human macrophages by chloroquine used alone and in combination with streptomycin, isoniazid, pyrazinamide, and two metabolites of vitamin D3

Abstract

Intracellular tubercle bacilli (TB) reside in vacuoles in infected human macrophages (MPs). The Tubercle bacilli (TB) in infected human macrophages (MPs) reside in vacuoles (4). These vacuoles might be phagolysosomes, which would be acidic and have several acid-dependent enzymes and activities (18). The presumed vacuolar acidity is thought to affect the activities of certain anti-TB drugs. It is supposed to decrease that of streptomycin (SM) (7) and increase that of pyrazinamide (PZA) (21,22,27).Chloroquine (CQ) is a drug which is widely used against malaria and certain kinds of chronic inflammatory diseases (3, 28). It is also used experimentally to study the acidic vacuoles of animal cells (16,24), because it is a lysosomotropic base (13, 28) which can increase the pH of these vacuoles and inhibit their acid-dependent activities (16,24). Thus, it inhibits malaria parasites by concentrating in the parasite's food vacuoles (lysosomes), raising their pH, and interfering with their digestive functions. This deprives the parasites of critical nutrients (13). Similarly, CQ can raise the pH of phagolysosomes in mammalian cells and affect their digestive functions (16,18,24). If TB do live in acid phagolysosomes in MPs and CQ can raise the pH of these vacuoles, then this drug should increase the anti-TB effectiveness of SM and lower that of PZA. This was tested in the experiments described here. While CQ enhanced the effectiveness of SM, as expected, it did not suppress that of PZA. Also, unexpectedly, it was itself able to inhibit TB in MPs, and it enhanced the anti-TB activity of another drug, isoniazid (INH), whose activity is not pH sensitive.(

Differential Modulation of Intracellular Survival of Cytosolic and Vacuolar Pathogens by Curcumin

“…Within endosomes, the acidic pH of the vacuole leads to its protonation and the protonated form of chloroquine gets trapped within endosomes (41). This concentrated chloroquine can kill bacteria within the phagocytic vacuole without any effect on cytosolic bacteria (7,10,26,35). We have shown that curcumin treatment prevents the escape of cytosolic bacteria, Shigella flexneri and Listeria monocytogenes, probably by stabilizing the endosomal membrane.…”

“…The survival assay was performed as described previously with some modifications (6,9). Briefly, overnight cultures of methicillin-resistant S. aureus (MRSA; strain COL) were diluted to 10 5 CFU in Mueller-Hinton medium. NaNO 2 and H 2 O 2 were freshly prepared at 200 mM, 1 mM, and 2 mM.…”

Chloroquine induces human mononuclear phagocytes to inhibit and kill Cryptococcus neoformans by a mechanism independent of iron deprivation.

“…Thus, the likelihood of resistance developing should be relatively small. Moreover, chloroquine may be beneficial for other intracellular pathogens that affect individuals with impaired cell-mediated immunity, as experimental data with several of these pathogens suggest (4)(5)(6)46). However, because chloroquine can interfere with effective antigen-processing (47), the greatest benefit might be in those patients with severely impaired T cell function, particularly individuals with AIDS and CD4ϩ T cell counts Ͻ 100/l blood.…”

Chloroquine induces human macrophage killing of Histoplasma capsulatum by limiting the availability of intracellular iron and is therapeutic in a murine model of histoplasmosis.

“…Likewise, chloroquine inhibits the growth ofMycobacterium tuberculosis in human MO and also significantly enhances the effectiveness of isoniazid and pyrazinamide against intracellular M. tuberculosis (43).…”