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Review
. 2020 Mar 4;84(2):e00070-19.
doi: 10.1128/MMBR.00070-19. Print 2020 May 20.

The Bewildering Antitubercular Action of Pyrazinamide

Elise A Lamont  1 , Nicholas A Dillon  1 , Anthony D Baughn  2
Affiliations
Review

The Bewildering Antitubercular Action of Pyrazinamide

Elise A Lamont et al. Microbiol Mol Biol Rev. .

Abstract

Pyrazinamide (PZA) is a cornerstone antimicrobial drug used exclusively for the treatment of tuberculosis (TB). Due to its ability to shorten drug therapy by 3 months and reduce disease relapse rates, PZA is considered an irreplaceable component of standard first-line short-course therapy for drug-susceptible TB and second-line treatment regimens for multidrug-resistant TB. Despite over 60 years of research on PZA and its crucial role in current and future TB treatment regimens, the mode of action of this unique drug remains unclear. Defining the mode of action for PZA will open new avenues for rational design of novel therapeutic approaches for the treatment of TB. In this review, we discuss the four prevailing models for PZA action, recent developments in modulation of PZA susceptibility and resistance, and outlooks for future research and drug development.

Keywords: antimicrobial activity; coenzyme A; drug resistance; drug resistance mechanisms; drug susceptibility; mode of action; pyrazinamide; tuberculosis.

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Figures

FIG 1
FIG 1
Proposed modes of antitubercular action of pyrazinamide. Pyrazinamide enters the cell by diffusion and is activated by the cytoplasmic pyrazinamidase/nicotinamidase PncA. Pyrazinoic acid has been proposed to act as a protonophore leading to the acidification of the bacterial cytoplasm (A), an inhibitor of fatty acid synthase I (B), an inhibitor of trans-translation (C), and/or an inhibitor of coenzyme A biosynthesis (D).
See this image and copyright information in PMC

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