title: Revisiting Anti-tuberculosis Activity of Pyrazinamide in Mice.
abstract: 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-replicatingMycobacterium 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 withM. 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 inM. 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.
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA ; KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Durban, South Africa.
authors.forename: Deepak V
authors.initials: DV
authors.lastname: Almeida
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Tyagi
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Si-Yang
authors.initials: S
authors.lastname: Li
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Durban, South Africa.
authors.forename: Kristina
authors.initials: K
authors.lastname: Wallengren
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Durban, South Africa.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Pym
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA ; KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Durban, South Africa.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Ammerman
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA ; KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Durban, South Africa.
authors.forename: William R
authors.initials: WR
authors.lastname: Bishai
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA ; KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Durban, South Africa.
authors.forename: Jacques H
authors.initials: JH
authors.lastname: Grosset