Capreomycin is active against non-replicating M. tuberculosis

Abstract

Background: Latent tuberculosis infection (LTBI) is affecting one-third of the world population, and activation of LTBI is a substantial source of new cases of tuberculosis. LTBI is caused by tubercle bacilli in a state of non-replicating persistence (NRP), and the goal of this study was to evaluate the activity in vitro of various antimicrobial agents against non-replicating M. tuberculosis.

Methods: To achieve a state of NRP we placed broth cultures of M. tuberculosis (three strains) in anaerobic conditions, and in this model tested all known anti-TB drugs and some other antimicrobial agents (a total of 32 drugs). The potential effect was evaluated by plating samples from broth cultures for determining the number of viable bacteria (CFU/ml) during a prolonged period of cultivation. Besides drug-free controls we used metronidazole for positive controls, the only drug known so far to be effective against tubercle bacilli in anaerobic setting.

Results: On a background of non-replicating conditions in drug-free cultures and clear bactericidal effect of metronidazole none of the antimicrobial agents tested produced effect similar to that of metronidazole except capreomycin, which was as bactericidal at the same level as metronidazole.

Conclusion: The unique ability of capreomycin to be bactericidal in vitro among the anti-TB drugs against non-replicating tubercle bacilli may justify the search for other drugs among peptide antibiotics with similar activity. This phenomenon requires further studies on the mechanism of action of capreomycin, and evaluation of its activity in appropriate animal models.

Figure 1

One of experiments confirming the validity of the anaerobic model: kinetics of CFU/ml of M. tuberculosis on days 0, 8, and 15 in 7H12 broth in anaerobic conditions: in drug-free control, in the presence of metronidazole (Met, 32 and 8 μg/ml), rifampin (RMP, 0.5 μg/ml), and isoniazid (INH, 0.5 μg/ml).

Figure 2

Kinetics of CFU/ml of M. tuberculosis in anaerobic conditions on days 0, 7, 14, and 21 in one of experiments with conventional anti-TB drugs compared to that of the drug-free control and effect of metronidazole (Met. 16 μg/ml): ethambutol (EMB, 8 μg/ml), streptomycin (SM, 8 μg/ml), and pyrazinamide (PZA, 900 μg/ml, at pH 6.0).

Figure 3

Effect of capreomycin (CM, at 8, 4, and 2 μg/ml) in one of experiments against M. tuberculosis (H37Rv) in anaerobic conditions compared to that of metronidazole (Met, 16 μg/ml)