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.
Pyrazinamide is one of the most important drugs to treat tuberculosis. Paradoxically, it is also the most difficult drug for which to detect whether a patiet has drug sensitive or resistant disease. We will demonstrate an ultra- rapid breath test for pyrazinamide sensitivity or resistance.
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