2. Academic Validation
  3. Inhibition of host PARP1 contributes to the anti-inflammatory and antitubercular activity of pyrazinamide

Inhibition of host PARP1 contributes to the anti-inflammatory and antitubercular activity of pyrazinamide

  • Nat Commun. 2023 Dec 9;14(1):8161. doi: 10.1038/s41467-023-43937-1.
Stefanie Krug 1 2,  Manish Gupta 1 2,  Pankaj Kumar 1 2,  Laine Feller 2,  Elizabeth A Ihms 1 2,  Bong Gu Kang 3 4,  Geetha Srikrishna 1 2,  Ted M Dawson 3 4 5 6,  Valina L Dawson 3 4 5 7,  William R Bishai 8 9
Affiliations

Affiliations

  • 1 Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 2 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 3 Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 4 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 5 Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 6 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 7 Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 8 Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
  • 9 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
PMID: 38071218 DOI: 10.1038/s41467-023-43937-1
Abstract

The Antibiotic pyrazinamide (PZA) is a cornerstone of tuberculosis (TB) therapy that shortens treatment durations by several months despite being only weakly bactericidal. Intriguingly, PZA is also an anti-inflammatory molecule shown to specifically reduce inflammatory cytokine signaling and lesion activity in TB patients. However, the target and clinical importance of PZA's host-directed activity during TB therapy remain unclear. Here, we identify the host Enzyme Poly(ADP-ribose) Polymerase 1 (PARP1), a pro-inflammatory master regulator strongly activated in TB, as a functionally relevant host target of PZA. We show that PZA inhibits PARP1 enzymatic activity in macrophages and in mice where it reverses TB-induced PARP1 activity in lungs to uninfected levels. Utilizing a PZA-resistant mutant, we demonstrate that PZA's immune-modulatory effects are PARP1-dependent but independent of its bactericidal activity. Importantly, PZA's bactericidal efficacy is impaired in PARP1-deficient mice, suggesting that immune modulation may be an integral component of PZA's antitubercular activity. In addition, adjunctive PARP1 inhibition dramatically reduces inflammation and lesion size in mice and may be a means to reduce lung damage and shorten TB treatment duration. Together, these findings provide insight into PZA's mechanism of action and the therapeutic potential of PARP1 inhibition in the treatment of TB.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16106
    99.89%, PARP Inhibitor