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Pyrazinamide
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Pyrazinamide is a prodrug that is converted into the active form, pyrazinoic acid, within M. tuberculosis by the action of pyrazinamidase, a nicotinamidase encoded by the gene pncA (Scorpio and Zhang, 1996). Pyrazinoic acid accumulates intracellularly at acid pH, suggesting a possible mechanism for the particular activity of pyrazinamide within acidic environments (Zhang et al., 2014). Mutations in the pncA gene of M. tuberculosis result in resistance to pyrazinamide, and many different mutations in pncA have been described, including in the upstream intergenic region (Scorpio et al., 1997; Wade and Zhang, 2004). M. bovis is naturally resistant to pyrazinamide because all strains have a mutation in pncA. The absence of pyrazinamidase activity can be used to detect pyrazinamide resistance in M. tuberculosis (Morlock et al., 2000). Strains of M. tuberculosis with a wild-type pncA sequence have been described that have phenotypically low-level pyrazinamide resistance but retain pyrazinamidase activity, and efflux mechanisms are also thought to play a role in mediating such resistance (Cheng et al., 2000).
Emerging therapeutic targets for treatment of leishmaniasis
Published in Expert Opinion on Therapeutic Targets, 2018
Recently, nicotinamidase, enzyme involved in assimilation of nicotinamide, nicotinic acid, and nicotinamide riboside, has been used to synthesize NAD+ by salvage pathway. It constitutes a key component of parasite development and virulence; add-back and mutational studies have attracted the scientific community for designing novel inhibitors and utilize this molecule as a therapeutic target [326]. Leishmania utilizes a purine pathway from the mammalian system using different nucleoside transporters. Phosphoribosyltransferases constitute a key component of the purine salvage pathway including three main enzymes: hypoxanthine-guanine phosphoribosyltransferase, xanthine phosphoribosyltransferase, and adenine phosphoribosyltransferase [327,328]. Leishmania has several enzymes for break down of host nucleosides, nucleotide, and nucleic acid before incorporation into its purine pools. Cloning, expression, and immunolocalization have led to characterization of several nucleoside hydrolases [329–331], several nucleases/nucleotidases that generates free nucleosides [332,333] thereby making the purine accessible for translocation through transporters into the parasite.