1887

Abstract

Pyrazinamide (PZA) is an unconventional front line tuberculosis drug characterized by high sterilizing activity, but poor activity. This disparity in PZA activity may reflect differences between the tissue environment and culture conditions. This study examined the effect of anaerobic conditions, which exist in granulomatous lesions , on PZA activity . Low oxygen enhanced the activity of PZA against , with anaerobic conditions resulting in greater enhancement than microaerobic conditions. ATPase and respiratory chain enzyme inhibitors enhanced PZA activity under normal atmospheric conditions, but not under anaerobic conditions. Furthermore, the inhibitors did not enhance isoniazid or rifampicin activity. Nitrate as an alternative electron acceptor antagonized PZA activity under anaerobic conditions. These findings provide further support for a proposed mechanism of action of PZA in which the active form of PZA (pyrazinoic acid) depletes the membrane energy reserve. They also provide another explanation for the higher sterilizing activity of PZA within lesions with low oxygen than under drug susceptibility testing conditions with ambient oxygen.

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2004-08-01
2024-04-20
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References

  1. Aisen P. 1980; The transferrins. In Iron in Biochemistry and Medicine pp 87–123 Edited by Jacobs A., Worwood M. London, UK: Academic Press;
    [Google Scholar]
  2. Canetti G. 1955 The Tubercle Bacillus in the Pulmonary Lesion of Man New York: Springer;
    [Google Scholar]
  3. Cole S. T., Brosch R., Parkhill J. & 39 other authors; 1998; Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537–544 [CrossRef]
    [Google Scholar]
  4. Heifets L., Lindholm-Levy P. 1992; Pyrazinamide sterilizing activity in vitro against semidormant Mycobacterium tuberculosis bacterial populations. Am Rev Respir Dis 145:1223–1225 [CrossRef]
    [Google Scholar]
  5. McDermott W., Tompsett R. 1954; Activation of pyrazinamide and nicotinamide in acidic environments in vitro . Am Rev Tuberc 70:748–754
    [Google Scholar]
  6. Mitchison D. 1985; The action of antituberculosis drugs in short-course chemotherapy. Tubercle 66:219–225 [CrossRef]
    [Google Scholar]
  7. Somoskovi A., Wade M. M., Sun Z., Zhang Y. 2004; Iron enhances the antituberculous activity of pyrazinamide. J Antimicrob Chemother 53:192–196 [CrossRef]
    [Google Scholar]
  8. Tarshis M. S., Weed W. A. Jr 1953; Lack of significant in vitro sensitivity of Mycobacterium tuberculosis to pyrazinamide on three different solid media. Am Rev Tuberc 67:391–395
    [Google Scholar]
  9. Wayne L. G., Hayes L. G. 1996; An in vitro model for sequential study of shiftdown of Mycobacterium tuberculosis through two stages of nonreplicating persistence. Infect Immun 64:2062–2069
    [Google Scholar]
  10. Zhang Y., Telenti A. 2000; Genetics of drug resistance in Mycobacterium tuberculosis . In Molecular Genetics of Mycobacteria pp 235–254 Edited by Hatfull G., Jacobs W. R. Jr Washington, DC: ASM Press;
    [Google Scholar]
  11. Zhang Y., Mitchison D. A. 2003; The curious characteristics of pyrazinamide: a review. Int J Tuberc Lung Dis 7:6–21
    [Google Scholar]
  12. Zhang Y., Scorpio A., Nikaido H., Sun Z. H. 1999; Role of acid pH and deficient efflux of pyrazinoic acid in the unique susceptibility of Mycobacterium tuberculosis to pyrazinamide. J Bacteriol 181:2044–2049
    [Google Scholar]
  13. Zhang Y., Permar S., Sun Z. 2002; Conditions that may affect the results of Mycobacterium tuberculosis susceptibility testing to pyrazinamide. J Med Microbiol 51:42–49
    [Google Scholar]
  14. Zhang Y., Wade M. M., Scorpio A., Zhang H., Sun Z. 2003; Mode of action of pyrazinamide: disruption of Mycobacterium tuberculosis membrane transport and energetics by pyrazinoic acid. J Antimicrob Chemother 52:790–795 [CrossRef]
    [Google Scholar]
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