The curious characteristics of pyrazinamide: a review.
The curious characteristics of pyrazinamide: a review.
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发表时间：
2003
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通讯作者：
Ying Zhang;D. Mitchison
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作者：
Ying Zhang;D. Mitchison
吡津酰胺(PZA)是一种重要的消毒结核病药物，有助于缩短目前结核病化疗方案的持续时间。当第一次被发现时，它在小鼠结核病中有活性，但在体外没有明显的活性，随后在治疗中的使用在很大程度上取决于康奈尔大学的经典实验，这些实验表明，它需要酸性pH才能发挥活性，并在小鼠身上具有杀菌活性。最近的研究表明，PZA通过被动扩散进入结核分枝杆菌，在烟酰胺酶/吡氨酰胺酶(PZase)的作用下转化为吡嗪酸(POA)，然后通过微弱的外排泵排出。质子化的POA(HPOA)在酸性条件下被重新吸收到细菌中并积累，因为外排泵效率低下，导致细胞损伤。与其他抗菌药不同，PZA没有明确的作用靶点。PZA对老化的细菌比对活跃生长的细菌更有效，可能是因为低细菌新陈代谢会减缓能量产生和外排泵的速度。本文综述了PZA在体外、巨噬细胞和动物模型中的活性。它描述了来自临床试验的证据，即它是一种与利福平协同作用的有效绝育药物。PZase基因(PncA)的高度多样性突变导致PZase活性丧失，导致PZA耐药性。综述了PZA或烟酰胺在液体和固体介质中的药敏试验、PZase活性试验或PncA突变试验的药敏测定方法。
Pyrazinamide (PZA) is an important sterilising tuberculosis drug that helps to shorten the duration of current chemotherapy regimens for tuberculosis. When first discovered, it had activity in murine tuberculosis but no apparent in vitro activity, and its subsequent use in treatment depended largely on classic experiments at Cornell University, which showed its requirement for an acid pH for activity and its sterilising activity in the mouse. Recent studies have shown that PZA enters Mycobacterium tuberculosis by passive diffusion, is converted to pyrazinoic acid (POA) by nicotinamidase/pyrazinamidase (PZase) and is then excreted by a weak efflux pump. Protonated POA (HPOA) is reabsorbed into the bacilli under acid conditions and accumulates because the efflux pump is inefficient, causing cellular damage. Unlike other antibacterials, PZA has no defined target of action. PZA is more active against old than against actively growing cultures, probably because the energy production and efflux pump would be slowed down by low bacterial metabolism. This review deals with the activity of PZA in vitro, in macrophages and in animal models. It describes the evidence from clinical trials that it is an effective sterilising drug that acts synergistically with rifampicin. The highly diverse mutations in the PZase gene (pncA) that lead to loss of PZase activity cause PZA resistance. Methods for susceptibility determination either as tests against PZA or nicotinamide in liquid and solid media, as tests for PZase activity or for mutations in pncA, are reviewed.