Anaerobic incubation conditions enhance pyrazinamide activity against Mycobacterium tuberculosis.
Anaerobic incubation conditions enhance pyrazinamide activity against Mycobacterium tuberculosis.
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DOI：
10.1099/jmm.0.45639-0
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发表时间：
2004-08
影响因子：
3
通讯作者：
M. Wade;Ying Zhang
中科院分区：
文献类型：
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作者：
M. Wade;Ying Zhang
吡嗪酰胺（PZA）是一种非传统的抗结核一线药物，其特点是体内杀菌活性高，但体外活性差。PZA活性的这种差异可能反映了体内组织环境和体外培养条件之间的差异。本研究检测了存在于体内肉芽肿病变中的厌氧条件对体外PZA活性的影响。低氧增强了PZA对结核分枝杆菌的活性，厌氧条件比微氧条件导致更大的增强。ATP酶和呼吸链酶抑制剂增强PZA活性在正常大气条件下，但不是在厌氧条件下。此外，抑制剂不增强异烟肼或利福平活性。在厌氧条件下，硝酸盐作为替代电子受体拮抗PZA活性。这些发现为PZA的拟议作用机制提供了进一步的支持，其中PZA的活性形式（吡嗪酸）耗尽了膜能量储备。它们还提供了另一种解释，即在低氧的体内病变内PZA的灭菌活性高于在环境氧的体外药物敏感性测试条件下的灭菌活性。
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.