The mechanism of action of
pyrazinamide, a key sterilizing
drug in the treatment of
tuberculosis, remains elusive;
pyrazinamide is a
pro-drug that requires activation by a bacterial-encoded
enzyme, and its activity is most apparent on non-replicating Mycobacterium tuberculosis. Recently, it has been suggested that
pyrazinamide might exert also some host-directed effect in addition to its antimicrobial activity. To address this possibility, three sequential experiments were conducted in immune-competent BALB/c and in immune-deficient, athymic nude mice. In the first experiment, BALB/c mice infected with M. bovis, which is naturally resistant to
pyrazinamide because it is unable to activate the
drug, were treated with standard
drug regimens with and without
pyrazinamide to specifically detect a host-directed effect. As no effect was observed,
pyrazinamide activity was compared in M.
tuberculosis-infected BALB/c and nude mice to determine whether the effect of
pyrazinamide would be reduced in the immune deficient mice. As
pyrazinamide did not appear to have any affect in the nude mice, a third experiment was performed in which
rifampin was replaced with
rifapentine (a similar
drug with a longer half-life) to permanently suppress mycobacterial growth. In these experimental conditions, the antimicrobial effect of
pyrazinamide was clear. Therefore, the results of our studies rule out a significant host-directed effect of
pyrazinamide in the TB infected host.