1887

Abstract

Pyrazinamide (PZA) is an unconventional front line tuberculosis drug characterized by high sterilizing activity, but poor activity. This disparity in PZA activity may reflect differences between the tissue environment and culture conditions. This study examined the effect of anaerobic conditions, which exist in granulomatous lesions , on PZA activity . Low oxygen enhanced the activity of PZA against , 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 lesions with low oxygen than under drug susceptibility testing conditions with ambient oxygen.

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2004-08-01
2019-12-10
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