Pyrazinamide Breath Test for TB

 描述（由申请人提供）：吡嗪酰胺（PZA）是治疗结核病（TB）的关键药物，因为其具有强效杀菌活性。PZA是一种前药，由吡嗪酰胺酶活化为抗分枝杆菌产物吡嗪酸（POA）和氨。对PZA的抗性由pncA中降低PZA活化的突变主导。PZA耐药性正变得非常令人关注，因为它在治疗中如此重要，耐药性正在增加，并且常规耐药性检测在实践中困难且缓慢。我们提出了一种快速，稳健，简单和即时护理（POC）的方法，提供生化PZA耐药数据在一个典型的病人-医生访问的时间。稳定同位素15 N-酰胺标记的PZA通过吸入器或雾化器直接递送至肺。然后，分枝杆菌吡嗪酰胺酶将其转化为POA和15 N-氨，然后呼出并在呼吸中检测。我们将进行体外和体内研究来表征和验证这种方法。

 DESCRIPTION (provided by applicant): Pyrazinamide (PZA) is a critical drug for treating tuberculosis (TB) because of its potent sterilizing activity. PZA is a prodrug, activated by pyrazinamidase to the antimycobacterial product pyrazinoic acid (POA) and ammonia. Resistance against PZA is dominated by mutations in pncA that decrease PZA activation. PZA resistance is becoming of great concern because it is so important in therapy, resistance is increasing and conventional resistance detection is difficult and slow in practice. We propose a rapid, robust, simple and point-of-care (POC) approach that delivers biochemical PZA resistance data during the time of a typical patient-doctor visit. Stable isotope 15N-amide labeled PZA is directly delivered to the lung by inhaler or nebulizer. Mycobacterial pyrazinamidase then converts it to POA and 15N-ammonia that is then exhaled and detected in breath. We will perform in vitro and in vivo studies to characterize and validate this approach.