摘要：自上世纪50年代以来，吡嗪酰胺就是用于结核病治疗的一线药物，但其发挥作用的机制却一直未得到很好的理解。中国复旦大学以及美国约翰斯•霍普金斯大学等机构的新研究解释了这种药物是如何消灭结核杆菌的。
研究人员发现，吡嗪酰胺进入患者体内后，通常会转化为具有活性的吡嗪酸。吡嗪酸可以绑定对结核杆菌至关重要的核糖体蛋白S1，阻止这种蛋白编码结核杆菌的脱氧核糖核酸，进而阻止结核杆菌产生维系其生存的其他蛋白。正是通过这种方式，吡嗪酰胺可以将通常持续9到12个月的结核病疗程缩短数个月。
这项研究成果8月12日发表在美国新一期《科学》杂志上。研究人员表示，这项研究解释了吡嗪酰胺的工作机制，有助于开发出更快治疗结核病的方法。
吡嗪酰胺是结核病疗法中唯一无法替换的药物，目前抗结核病的所有候选药物都通过与吡嗪酰胺联合使用才能获得最佳疗效。
生物探索推荐英文论文摘要：
Pyrazinamide Inhibits Trans-Translation in Mycobacterium tuberculosis
ABSTRACT
Pyrazinamide (PZA) is a first-line tuberculosis drug that plays a unique role in shortening the duration of tuberculosis chemotherapy. PZA is hydrolyzed intracellularly to pyrazinoic acid (POA) by pyrazinamidase (PZase, encoded by pncA), an enzyme frequently lost in PZA-resistant strains, but the target of POA in Mycobacterium tuberculosis has remained elusive. Here, we identify a new target of POA as the ribosomal protein S1 (RpsA), a vital protein involved in protein translation and the ribosome-sparing process of trans-translation. Three PZA-resistant clinical isolates without pncA mutation harbored RpsA mutations. RpsA overexpression conferred increased PZA resistance, and we confirmed that POA bound to RpsA (but not a clinically identified ΔAla mutant) and subsequently inhibited trans-translation rather than canonical translation. Trans-translation is essential for freeing scarce ribosomes in nonreplicating organisms, and its inhibition may explain the ability of PZA to eradicate persisting organisms.
