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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI117224-02
Application #
9008021
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lacourciere, Karen A
Project Start
2015-02-05
Project End
2017-01-31
Budget Start
2016-02-01
Budget End
2017-01-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of New Mexico Health Sciences Center
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
829868723
City
Albuquerque
State
NM
Country
United States
Zip Code
87131