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Chapter 24 : Mechanisms of Pyrazinamide Action and Resistance

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Abstract:

Pyrazinamide (PZA), a nicotinamide analogue ( Fig. 1 ), was first chemically synthesized in 1936 ( ), but its antituberculosis (anti-TB) potential was not recognized until 1952 ( ). Its discovery as a TB drug was based on a serendipitous observation that nicotinamide had certain activity against mycobacteria in animal models ( ). Subsequent synthesis of nicotinamide analogues and direct testing in the mouse model of TB infection without testing led to the identification of PZA as an active agent ( ). Before the 1970s, PZA was mainly used as a second-line TB drug for the treatment of drug-resistant TB or in treatment of relapsed TB because of the hepatic toxicity caused by a higher PZA dosage (3.0 g daily) and longer treatment used in earlier clinical studies. However, largely encouraged by the impressive mouse studies by McDermott and colleagues that demonstrated high sterilizing activity of PZA in combination with isoniazid (INH) ( ), the British Medical Research Council conducted clinical trials in East Africa with lower PZA doses (1.5 to 2.0 g daily), which are not significantly hepatotoxic. PZA was found to be almost as effective as rifampin (RIF) as a sterilizing drug, as judged by more frequent sputum conversion at 2 months and by the relapse rates. Subsequent clinical studies showed that the effects of RIF and PZA were synergistic. These studies showed that treatment could be shortened from 12 months or more to 9 months if either RIF or PZA was added to the regimen, and to 6 months if both were included ( ). PZA has since been used as a first-line agent for treatment of drug-susceptible TB with RIF, INH, and ethambutol, which is currently the best TB therapy. PZA is also an integral component of treatment regimens for multidrug-resistant (MDR) TB ( ) and of any new regimens in conjunction with new TB drug candidates in clinical trials ( ).

Citation: Zhang Y, Shi W, Zhang W, Mitchison D. 2014. Mechanisms of Pyrazinamide Action and Resistance, p 479-491. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0023-2013
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Figures

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Figure 1

Conversion of nicotinamide and PZA to nicotinic acid and POA, respectively, by the enzyme PZase/nicotinamidase (PncA) encoded by the gene.

Citation: Zhang Y, Shi W, Zhang W, Mitchison D. 2014. Mechanisms of Pyrazinamide Action and Resistance, p 479-491. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0023-2013
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Image of Figure 2
Figure 2

Mode of action of PZA. PZA enters tubercle bacilli by passive diffusion, where it is converted to POA by PZase/nicotinamidase encoded by the gene. POA then reaches the cell surface through passive diffusion and a weak (deficient) efflux mechanism. At acid pH, the protonated POA (HPOA) enters the cell in a pH-dependent manner by passive diffusion and then accumulates to high levels intracellularly and kills by multiple mechanisms including disruption of membrane energy production, inhibition of trans-translation, possibly inhibition of pantothenate and CoA biosynthesis, and other as yet unidentified mechanisms.

Citation: Zhang Y, Shi W, Zhang W, Mitchison D. 2014. Mechanisms of Pyrazinamide Action and Resistance, p 479-491. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0023-2013
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Figure 3

Diverse mutations scattered along the gene in PZA-resistant The mutations were obtained from the Drug Resistance Mutation Database (http://www.tbdreamdb.com).

Citation: Zhang Y, Shi W, Zhang W, Mitchison D. 2014. Mechanisms of Pyrazinamide Action and Resistance, p 479-491. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0023-2013
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Tables

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Table 1

Increased PZA susceptibility of mutants with a defect in energy metabolism

Citation: Zhang Y, Shi W, Zhang W, Mitchison D. 2014. Mechanisms of Pyrazinamide Action and Resistance, p 479-491. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0023-2013

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