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
1. Gouzy A#*, Li S#, Chen J, Na A, Saleh A, Azadian ZA, Tam K, Munsamy-Govender V, Poulton NC, DeJesus MA, Schnappinger D, Rhee KY, Ehrt S*, Rock JM*. (2026). Metabolic control of drug resistance by a mycobacterial ion channel. bioRxiv. doi: 10.64898/2026.03.10.710584
2. Laudouze J, Rokitskaya TI, Abolet A, Point V, Firsov AM, Khailova LS, Cavalier JF, Canaan S, Baulard AR, Antonenko YN, Gouzy A#, Santucci P#. (2026). Pyrazinamide kills Mycobacterium tuberculosis via pH-driven weak-acid permeation and cytosolic acidification. bioRxiv. doi: 10.1101/2025.09.26.678883
3. Ma R, Vásquez D, Ocius K, Naick A, Healy C, Ioerger TR, Pires M, Cava F, Gouzy A#, Ehrt S#. (2026). Non-canonical peptidoglycan cross-linking is essential for Mycobacterium tuberculosis acid resistance. bioRxiv. doi: 10.64898/2026.03.16.712108
4. Gouzy A#, Healy C#, Black KA, Rhee KY, Ehrt S. (2021). Growth of Mycobacterium tuberculosis at acidic pH depends on lipid assimilation and is accompanied by reduced GAPDH activity. Proceedings of the National Academy of Sciences USA.118(32): e2024571118. doi: 10.1073 PMID: 34341117