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dc.contributor.authorAnthony, R Men
dc.contributor.authorden Hertog, A Len
dc.contributor.authorvan Soolingen, Den
dc.date.accessioned2018-03-22T11:58:58Z
dc.date.available2018-03-22T11:58:58Z
dc.date.issued2018-03-08
dc.identifier.citation'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? 2018 J. Antimicrob. Chemother.en
dc.identifier.issn1460-2091
dc.identifier.pmid29528413
dc.identifier.doi10.1093/jac/dky060
dc.identifier.urihttp://hdl.handle.net/10029/621682
dc.description.abstractA 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.
dc.language.isoenen
dc.rightsArchived with thanks to The Journal of antimicrobial chemotherapyen
dc.title'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?en
dc.typeArticleen
dc.identifier.journalTijdschrift J Antimicrob Chemother 2018; advance online publication (ahead of print)en
html.description.abstractA 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.


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