Pyrazinamide and Pyrazinoic Acid Activity against Tubercle Bacilli in Cultured Human Macrophages and in the BACTEC System

Abstract

Pyrazinamide (PZA) has becomean essential component of current 6-month regimens for therapy of tuberculosis. Susceptible strains of tubercle bacilliconvert PZA to pyrazinoic acid (POA)through pyrazinamidase (PZase), which resistant strains and Mycobacterium bovis bacilleCalmette-Guerin lack. PZA susceptibility results obtained in cultured human macrophages were compared with those in the broth BACTEC system with 7H12 medium at pH 6.0 for strains known to bePZasepositive or -negative. Although added PDA was unable to inhibit tubercle bacilli in cultured macrophages, it was able to inhibit them at very high concentrations in the BACTEC broth. Intracellularly formed PDA would not be able to escape from the macrophage, and therefore would accumulate sufficiently to lower pH to toxic levels for tubercle bacilli. The results suggest that the cultured macrophages contribute actively or passively to the effectiveness of PZA, such as through the proposed mechanism of low pH generated by PZase in the phagolysosomes.