Pyrazinamide kills <i>Mycobacterium tuberculosis</i> via pH-driven weak-acid permeation and cytosolic acidification.

ABSTRACT: Pyrazinamide (PZA) is a cornerstone drug in tuberculosis (TB) treatment with a strong bactericidal activity in vivo on both actively and non-replicating bacterial subpopulations. Yet the precise mode of action of its active form, pyrazinoic acid (HPOA), remains unclear. In this study, we comprehensively explore and challenge the two major and conflicted models of PZA mode of action. The pH-dependent model, where the drug is mostly effective at acidic pH by acidifying Mycobacterium tuberculosis (Mtb) cytosol, and the PanD-dependent model where PZA's active form targets the aspartate decarboxylase PanD, therefore depleting pantothenate and subsequently coenzyme A (CoA) levels regardless of the surrounding pH. By combining standard antimicrobial susceptibility testing at

SUBMITTER: Laudouze J 

PROVIDER: S-EPMC12486132 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature