Thiol Stress Fuels Pyrazinamide Action Against Mycobacterium tuberculosis
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Pyrazinamide (PZA) is a cornerstone of first-line antitubercular drug therapy and is unique in its ability to kill nongrowing populations of Mycobacterium tuberculosis through disruption of coenzyme A synthesis. Unlike other drugs, PZA action is conditional and requires potentiation by host-relevant environmental stressors, such as low pH and nutrient limitation. Despite its pivotal role in tuberculosis therapy, the mechanistic basis for PZA potentiation remains unknown and the durability of this crucial drug is challenged by the emergent spread of drug resistance. To advance our understanding of PZA action and facilitate discovery efforts, we characterized the activity of a more potent PZA analog, morphazinamide (MZA). Here, we demonstrate that like PZA, MZA acts in part through impairment of coenzyme A synthesis. Unexpectedly, we find that, in contrast to PZA, MZA does not require potentiation due to aldehyde-mediated disruption of thiol metabolism and maintains bactericidal activity against PZA-resistant strains. Our findings reveal a novel dual action mechanism of MZA that synergistically disrupts coenzyme A synthesis resulting in a faster rate of killing and a higher barrier to resistance relative to PZA. Together, these observations resolve the mechanistic basis for potentiation of a key first-line antitubercular drug and provide new insights for discovery of improved therapeutic approaches for tuberculosis.
Significance Statement
Pyrazinamide is the only antitubercular drug of its kind, capable of targeting persistent Mycobacterium tuberculosis through disruption of the coenzyme A biosynthetic pathway. A peculiar feature of this drug is that its activity is conditional, requiring low pH for its action. Despite decades of investigation, the precise basis for this conditional susceptibility has remained elusive which has been a barrier to discovery of more effective next-generation analogs. Using approaches in chemical biology, functional genomics and bacterial physiology we demonstrate that activation of thiol stress is the basis for pyrazinamide potentiation. These findings resolve a long-standing question regarding the mechanistic basis for conditional PZA susceptibility of M. tuberculosis and reveal novel avenues for antimicrobial drug discovery efforts.
