Pyrazinamide and pyrazinoic acid activity against tubercle bacilli in cultured human macrophages and in the BACTEC system.
Pyrazinamide (PZA) has become an essential component of current 6-month regimens for therapy of tuberculosis. Susceptible strains of tubercle bacilli convert PZA to pyrazinoic acid (POA) through pyrazinamidase (PZase), which resistant strains and Mycobacterium bovis bacille Calmette-Guérin 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 be PZase-positive or -negative. Although added POA 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 POA 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.
Salfinger
M
M
Webb-Waring Lung Institute, University of Colorado Health Sciences Center, Denver.
Crowle
A J
AJ
Reller
L B
LB
D000581:Amidohydrolases / Q000378:metabolism; D002478:Cells, Cultured; D003470:Culture Media; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008264:Macrophages / Q000382:microbiology*; D009163:Mycobacterium bovis / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D011718:Pyrazinamide / Q000031:analogs & derivatives* / Q000494:pharmacology*
D003470:Culture Media; D011718:Pyrazinamide; C005296:pyrazinoic acid; D000581:Amidohydrolases; C022490:pyrazinamide deamidase