Somoskovi Akos, Wade Mary Margaret, Sun Zhonghe, Zhang Ying
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
J Antimicrob Chemother. 2004 Feb;53(2):192-6. doi: 10.1093/jac/dkh042. Epub 2004 Jan 16.
Pyrazinamide is a paradoxical frontline tuberculosis drug characterized by high in vivo sterilizing activity but poor in vitro activity. This separation in pyrazinamide activity reflects differences between the in vivo tissue environment and in vitro culture conditions. The well-known acid pH requirement for pyrazinamide activity was discovered previously based on such reasoning but does not completely explain the discrepancy between in vivo and in vitro activity of pyrazinamide. This study examined the effect of iron, which could potentially be elevated in local inflammatory lesions, on pyrazinamide activity in vitro.
The effect of iron on the activity of pyrazinamide or its active derivative pyrazinoic acid against Mycobacterium tuberculosis was assessed in liquid medium in a drug exposure assay or in solid medium with pyrazinamide plus iron or pyrazinamide alone. The effect of iron on pyrazinamide or pyrazinoic acid was expressed as percentage of growth inhibition.
We have shown that iron enhances the activity of pyrazinamide and pyrazinoic acid against M. tuberculosis in both liquid and solid media at acid pH 5.6. Iron enhanced the activity of pyrazinoic acid but not pyrazinamide against the naturally pyrazinamide-resistant Mycobacterium bovis BCG. Other metal ions such as magnesium, calcium and zinc did not enhance the activity of pyrazinamide or pyrazinoic acid.
Iron increased the activity of pyrazinamide or pyrazinoic acid against M. tuberculosis in vitro. These findings may have implications for the study of mechanism of action of pyrazinamide and possible iron supplement for improving the activity of pyrazinamide.
吡嗪酰胺是一种具有矛盾特性的一线抗结核药物，其体内杀菌活性高但体外活性差。吡嗪酰胺活性的这种差异反映了体内组织环境与体外培养条件之间的不同。基于此类推理，先前已发现吡嗪酰胺活性对酸性pH的众所周知的需求，但这并不能完全解释吡嗪酰胺体内和体外活性之间的差异。本研究考察了在局部炎症病变中可能升高的铁对吡嗪酰胺体外活性的影响。
在药物暴露试验的液体培养基中或在含有吡嗪酰胺加铁或仅含吡嗪酰胺的固体培养基中，评估铁对吡嗪酰胺或其活性衍生物吡嗪酸抗结核分枝杆菌活性的影响。铁对吡嗪酰胺或吡嗪酸的影响以生长抑制百分比表示。
我们已表明，在酸性pH 5.6的液体和固体培养基中，铁均可增强吡嗪酰胺和吡嗪酸对结核分枝杆菌的活性。铁增强了吡嗪酸对天然耐吡嗪酰胺的牛分枝杆菌卡介苗的活性，但未增强吡嗪酰胺的活性。其他金属离子如镁、钙和锌并未增强吡嗪酰胺或吡嗪酸的活性。
铁在体外增加了吡嗪酰胺或吡嗪酸对结核分枝杆菌的活性。这些发现可能对吡嗪酰胺作用机制的研究以及改善吡嗪酰胺活性的可能的铁补充剂具有启示意义。
