Alexandre Gouzy
Weill Cornell Medical College, New York, USA
Shedding light on pyrazinamide’s mode of action and resistance
The infection microenvironment (e.g. pH and nutrient availability) can profoundly shape antibiotic efficacy by altering drug chemistry and bacterial physiology. Yet, most mechanistic studies rely on artificial media that fail to mimic host conditions. Pyrazinamide (PZA), a cornerstone of tuberculosis therapy, exemplifies this challenge: its potent sterilizing activity in vivo contrasts with poor performance in standard in vitro assays, obscuring its mode of action and resistance detection. To address this, we developed a lipid-rich and acidic culture medium that recapitulates host-relevant conditions and enables robust measurement of PZA activity. Using this platform, we demonstrate that acidic pH is indispensable for PZA-mediated killing and identified clinically relevant bacterial genetic determinants of PZA resistance. These findings underscore the need for physiologically relevant models to advance antibiotic research and combat drug resistance.