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J Antimicrob Chemother. 2018 Jul 1;73(7):1750-1754. doi: 10.1093/jac/dky060.

'Happy the man, who, studying nature's laws, Thro' known effects can trace the secret cause.' Do we have enough pieces to solve the pyrazinamide puzzle?

Author information

1
National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
2
Institute for Life Sciences and Chemistry, HU University of Applied Sciences Utrecht, Utrecht, The Netherlands.

Abstract

A low pH was assumed to be required for the activity of pyrazinoic acid (the active form of pyrazinamide) against Mycobacterium tuberculosis, but recently activity has been demonstrated at neutral pH. Renewed interest in pyrazinamide has led to an increasing number of potential targets and the suspicion that pyrazinamide is a 'dirty drug'. However, it is our opinion that the recent demonstration that pyrazinoic acid is active against PanD provides an alternative explanation for the secret of pyrazinamide's unusual activity. In this article we propose that PanD is the primary target of pyrazinoic acid but expression of pyrazinoic acid susceptibility requires an intact stress response. As the mycobacterial stress response requires the interaction of a number of genes, disruption of any could result in an inability to enter the susceptible phenotype. We believe this model can explain most of the recent observations of the seemingly diverse spectrum of activity of pyrazinamide.

PMID:
29528413
DOI:
10.1093/jac/dky060

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