Analysis of a novel pncA mutation for susceptibility to Pyrazinamide therapy
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Peer-reviewed
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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.
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Keywords
pyrazinamide resistance, structural bioinformatics, pncA mutations, tuberculosis treatment
Journal Title
American Journal of Respiratory and Critical Care Medicine
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1073-449X
1535-4970
1535-4970
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American Thoracic Society
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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).