# The impact of pyrazinamide on metabolism in Mycobacterium tuberculosis

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2022 · $459,133

## Abstract

Project Summary
Pyrazinamide (PZA) is a critical component of first-line tuberculosis (TB) therapy because it has dramatically
reduced relapse rates and treatment duration. PZA is weakly active in vitro, but potently sterilizing in vivo, due
to its outstanding activity against slow and non-replicating populations of Mycobacterium tuberculosis that are
phenotypically tolerant to most other TB drugs. Understanding the basis for the in vivo sterilizing activity of PZA
represents one of the most important unmet needs in TB drug discovery. While the mode of action of PZA
remains under investigation, our knowledge of factors that govern susceptibility and resistance has advanced
considerably in recent years. PZA is a pro-drug that must be converted to the active form of pyrazinoic acid
(POA) by the M. tuberculosis amidase PncA, and loss-of-function mutations in pncA account for at least 70%
of clinical resistance. Other genetic variations associated with resistance have been described, but most have
not been evaluated in isogenic strains to determine their role in resistance, and have not been assessed for
association with PZA resistance in animal models of infection. Importantly, PZA lacks antitubercular activity in
athymic nude mice, indicating a key role for T cell-mediated immunity in efficacy. Consistent with these
observations, our lab and others have shown that PZA is inactive against M. tuberculosis in resting
macrophages, but contributes to bacterial killing in macrophages activated by interferon-gamma (IFN-ɣ). Host-
dependent stressors that are associated with IFN-ɣ stimulation, such as exposure to low pH, nutrient limitation
and reactive oxygen species, have been implicated as contributors to PZA action. Our recent studies have
revealed a central role for specific M. tuberculosis stress responses in PZA conditional susceptibility. Through
these studies, we have identified a network of functions that modulates PZA susceptibility when expression of
the corresponding genes is altered. We have also identified specific host factors that contribute to PZA action
in macrophages and in infected mice. Based on these findings, we have identified means to bolster drug action
under conditions where PZA typically lacks activity. Through this proposal, we aim to characterize novel
molecular mechanisms for PZA resistance, determine host factors that modulate PZA susceptibility, and
assess opportunities in host- and microbe-targeted PZA potentiation. These studies will advance our
understanding of mechanisms that govern PZA susceptibility and resistance of M. tuberculosis. As a
substantial proportion of TB disease results from impaired T cell responses, it is of fundamental importance to
understand how these responses relate to PZA efficacy and how we can use this information to optimize PZA
action in the context of impaired immunity.

## Key facts

- **NIH application ID:** 10369701
- **Project number:** 5R01AI123146-07
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** ANTHONY D BAUGHN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $459,133
- **Award type:** 5
- **Project period:** 2021-03-10 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10369701

## Citation

> US National Institutes of Health, RePORTER application 10369701, The impact of pyrazinamide on metabolism in Mycobacterium tuberculosis (5R01AI123146-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10369701. Licensed CC0.

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