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

Stefanie Krug, Manish Gupta, Pankaj Kumar, Laine Feller, Elizabeth A. Ihms, Bong Gu Kang, Geetha Srikrishna, Ted M. Dawson, Valina L. Dawson and William R. Bishai ()
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Stefanie Krug: Johns Hopkins University School of Medicine
Manish Gupta: Johns Hopkins University School of Medicine
Pankaj Kumar: Johns Hopkins University School of Medicine
Laine Feller: Johns Hopkins University School of Medicine
Elizabeth A. Ihms: Johns Hopkins University School of Medicine
Bong Gu Kang: Johns Hopkins University School of Medicine
Geetha Srikrishna: Johns Hopkins University School of Medicine
Ted M. Dawson: Johns Hopkins University School of Medicine
Valina L. Dawson: Johns Hopkins University School of Medicine
William R. Bishai: Johns Hopkins University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43937-1

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