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Analysis of a novel pncA mutation for susceptibility to Pyrazinamide therapy

Accepted version
Peer-reviewed

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Type

Article

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Authors

Karmakar 
Globan 
Fyfe 
Stinear 
Johnson 

Abstract

Pyrazinamide (PZA), which is an analogue of nicotinamide, is an important first-line drug used in the short-course treatment of tuberculosis. PZA is a prodrug devoid of significant antibacterial activity. It is metabolized into its active form, pyrazinoic acid (POA), by the amidase activity of the Mycobacterium tuberculosis nicotinamidase/pyrazinamidase, encoded by the pncA gene. Mutations in pncA that prevent activation of the prodrug represent the major mechanism of PZA resistance in M. tuberculosis [1]. This antibiotic plays a key role in shortening the duration of anti-tuberculous treatment due to its activity against the persisting tubercle bacilli at acidic pH.

Description

Keywords

pyrazinamide resistance, structural bioinformatics, pncA mutations, tuberculosis treatment

Journal Title

American Journal of Respiratory and Critical Care Medicine

Conference Name

Journal ISSN

1073-449X
1535-4970

Volume Title

Publisher

American Thoracic Society
Sponsorship
Medical Research Council (MR/M026302/1)
M.K. was supported by the Melbourne Research Scholarship from the University of Melbourne. D.B.A was funded by a Newton Fund RCUK-CONFAP Grant awarded by The Medical Research Council (MRC) and Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) (MR/M026302/1), the Jack Brockhoff Foundation (JBF 4186, 2016), and a C. J Martin Research Fellowship from the National Health and Medical Research Council of Australia (APP1072476).