The molecular basis of pyrazinamide activity on Mycobacterium tuberculosis PanD.,Nature Communications

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The molecular basis of pyrazinamide activity on Mycobacterium tuberculosis PanD.
Nature Communications ( IF 14.7 ) Pub Date : 2020-01-17 , DOI: 10.1038/s41467-019-14238-3
Qingan Sun ₁ , Xiaojun Li ₁ , Lisa M Perez ₂ , Wanliang Shi ₃ , Ying Zhang ₃ , James C Sacchettini ₁

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Pyrazinamide has been a mainstay in the multidrug regimens used to treat tuberculosis. It is active against the persistent, non-replicating mycobacteria responsible for the protracted therapy required to cure tuberculosis. Pyrazinamide is a pro-drug that is converted into pyrazinoic acid (POA) by pyrazinamidase, however, the exact target of the drug has been difficult to determine. Here we show the enzyme PanD binds POA in its active site in a manner consistent with competitive inhibition. The active site is not directly accessible to the inhibitor, suggesting the protein must undergo a conformational change to bind the inhibitor. This is consistent with the slow binding kinetics we determined for POA. Drug-resistant mutations cluster near loops that lay on top of the active site. These resistant mutants show reduced affinity and residence time of POA consistent with a model where resistance occurs by destabilizing the closed conformation of the active site.

中文翻译：

吡嗪酰胺对结核分枝杆菌PanD活性的分子基础。

吡嗪酰胺一直是用于治疗结核病的多种药物疗法的主体。它对治疗结核病所需的长期治疗所致的持久性非复制型分枝杆菌具有活性。吡嗪酰胺是一种前药，可通过吡嗪酰胺酶转化为吡嗪酸（POA），但是，该药物的确切靶标难以确定。在这里，我们显示了PanD酶以与竞争抑制相一致的方式在其活性位点结合POA。抑制剂不能直接进入活性位点，表明该蛋白质必须经历构象变化才能结合抑制剂。这与我们确定的POA缓慢的结合动力学是一致的。耐药突变聚集在位于活性位点顶部的环附近。

更新日期：2020-01-17

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