Dr. Alexandre Gouzy - Mimicking the Infection Environment to Improve Drug Resistance Detection: The Case of the Antitubercular Drug Pyrazinamide - IPBS-Toulouse, Seminar Room

Alexandre Gouzy

Weill Cornell Medical College, New York, USA

Mimicking the Infection Environment to Improve Drug Resistance Detection: The Case of the Antitubercular Drug Pyrazinamide

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.

Selected references

• Gouzy et al. (2021) Growth of Mycobacterium tuberculosis at acidic pH depends on lipid assimilation and is accompanied by reduced GAPDH activity. Proc Natl Acad Sci USA 118(32):e2024571118 doi: 10.1073/pnas.2024571118
• Laudouze et al. (2025) Pyrazinamide kills Mycobacterium tuberculosis via pH-driven weak-acid permeation and cytosolic acidification. bioRxiv doi: 10.1101/2025.09.26.678883
• Gouzy et al. (2025) Metabolic control of drug resistance by a mycobacterial ion channel. bioRxiv doi: 10.64898/2026.03.10.710584