Anaerobic incubation conditions enhance pyrazinamide activity against Mycobacterium tuberculosis.
Pyrazinamide (PZA) is an unconventional front line tuberculosis drug characterized by high in vivo sterilizing activity, but poor in vitro activity. This disparity in PZA activity may reflect differences between the in vivo tissue environment and in vitro culture conditions. This study examined the effect of anaerobic conditions, which exist in granulomatous lesions in vivo, on PZA activity in vitro. Low oxygen enhanced the activity of PZA against Mycobacterium tuberculosis, with anaerobic conditions resulting in greater enhancement than microaerobic conditions. ATPase and respiratory chain enzyme inhibitors enhanced PZA activity under normal atmospheric conditions, but not under anaerobic conditions. Furthermore, the inhibitors did not enhance isoniazid or rifampicin activity. Nitrate as an alternative electron acceptor antagonized PZA activity under anaerobic conditions. These findings provide further support for a proposed mechanism of action of PZA in which the active form of PZA (pyrazinoic acid) depletes the membrane energy reserve. They also provide another explanation for the higher sterilizing activity of PZA within in vivo lesions with low oxygen than under in vitro drug susceptibility testing conditions with ambient oxygen.
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
Mary Margaret
MM
Wade
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
Ying
Y
Zhang
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000693:Anaerobiosis; D000995:Antitubercular Agents / Q000494:pharmacology; D015169:Colony Count, Microbial; D004579:Electron Transport / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007538:Isoniazid / Q000494:pharmacology; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism*; D009566:Nitrates / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D011718:Pyrazinamide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D012293:Rifampin / Q000494:pharmacology
D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D009566:Nitrates; D011718:Pyrazinamide; C005296:pyrazinoic acid; D000251:Adenosine Triphosphatases; D010100:Oxygen; D007538:Isoniazid; D012293:Rifampin