Mode of action of pyrazinamide:: disruption of Mycobacterium tuberculosis membrane transport and energetics by pyrazinoic acid
Mode of action of pyrazinamide:: disruption of Mycobacterium tuberculosis membrane transport and energetics by pyrazinoic acid
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DOI：
10.1093/jac/dkg446
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发表时间：
2003-11-01
影响因子：
5.2
通讯作者：
Sun, ZH
中科院分区：
文献类型：
--
作者：
Zhang, Y;Wade, MM;Sun, ZH
吡嗪酰胺是一种缩短结核病治疗时间的重要灭菌药物。然而，由于吡嗪酰胺的特殊性质，其作用机制尚不清楚。本研究表明，吡嗪酰胺的活性部分吡嗪酸破坏了结核分枝杆菌的膜能量，抑制了膜运输功能。吡嗪酰胺对老年非复制杆菌的优先活性与其低膜电位、吡嗪酸和酸ph对膜电位的破坏有关。膜能量学抑制剂提高了吡嗪酰胺的抗结核活性。这些发现揭示了吡嗪酰胺的作用模式，并可能有助于设计缩短治疗时间的新药。
Pyrazinamide is an important sterilizing drug that shortens tuberculosis (TB) therapy. However, the mechanism of action of pyrazinamide is poorly understood because of its unusual properties. Here we show that pyrazinoic acid, the active moiety of pyrazinamide, disrupted membrane energetics and inhibited membrane transport function in Mycobacterium tuberculosis. The preferential activity of pyrazinamide against old non-replicating bacilli correlated with their low membrane potential and the disruption of membrane potential by pyrazinoic acid and acid pH. Inhibitors of membrane energetics increased the antituberculous activity of pyrazinamide. These findings shed new light on the mode of action of pyrazinamide and may help in the design of new drugs that shorten therapy.