Skip to main content
PMC home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1995 Jun;39(6):1269–1271. doi: 10.1128/aac.39.6.1269

Activity of n-propyl pyrazinoate against pyrazinamide-resistant Mycobacterium tuberculosis: investigations into mechanism of action of and mechanism of resistance to pyrazinamide.

R J Speirs 1, J T Welch 1, M H Cynamon 1
PMCID: PMC162725  PMID: 7574514

Abstract

The mechanism of action of pyrazinamide (PZA) is not known. One hypothesis is that PZA functions as a prodrug of pyrazinoic acid. Susceptibility to PZA correlates with amidase activity of the Mycobacterium tuberculosis isolate in question. PZA-resistant isolates retain susceptibility in vitro to pyrazinoic acid and n-propyl pyrazinoate. Esters of pyrazinoic acid appear to circumvent the requirement for activation by mycobacterial amidase. The MICs of n-propyl pyrazinoate for M. tuberculosis isolates are lower than those of pyrazinoic acid. Further studies to assess the effects of modifications of the alcohol and pyrazine moieties of pyrazinoate esters on in vitro and in vivo antituberculosis activity are under way. This may lead to a candidate compound with enhanced activity against both PZA-susceptible and PZA-resistant M. tuberculosis isolates suitable for clinical development.

Full Text

The Full Text of this article is available as a PDF (210.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bass J. B., Jr, Farer L. S., Hopewell P. C., O'Brien R., Jacobs R. F., Ruben F., Snider D. E., Jr, Thornton G. Treatment of tuberculosis and tuberculosis infection in adults and children. American Thoracic Society and The Centers for Disease Control and Prevention. Am J Respir Crit Care Med. 1994 May;149(5):1359–1374. doi: 10.1164/ajrccm.149.5.8173779. [DOI] [PubMed] [Google Scholar]
  2. Butler W. R., Kilburn J. O. Susceptibility of Mycobacterium tuberculosis to pyrazinamide and its relationship to pyrazinamidase activity. Antimicrob Agents Chemother. 1983 Oct;24(4):600–601. doi: 10.1128/aac.24.4.600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cynamon M. H., Klemens S. P., Chou T. S., Gimi R. H., Welch J. T. Antimycobacterial activity of a series of pyrazinoic acid esters. J Med Chem. 1992 Apr 3;35(7):1212–1215. doi: 10.1021/jm00085a007. [DOI] [PubMed] [Google Scholar]
  4. DESSAU F. I., YEAGER R. L., BURGER F. J., WILLIAMS J. H. Pyrazinamide (aldinamide) in experimental tuberculosis of the guinea pig. Am Rev Tuberc. 1952 May;65(5):519–522. [PubMed] [Google Scholar]
  5. David H. L. Basis for lack of drug susceptibility of atypical mycobacteria. Rev Infect Dis. 1981 Sep-Oct;3(5):878–884. doi: 10.1093/clinids/3.5.878. [DOI] [PubMed] [Google Scholar]
  6. Davidson P. T., Le H. Q. Drug treatment of tuberculosis--1992. Drugs. 1992 May;43(5):651–673. doi: 10.2165/00003495-199243050-00003. [DOI] [PubMed] [Google Scholar]
  7. Grosset J. Present and new drug regimens in chemotherapy and chemoprophylaxis of tuberculosis. Bull Int Union Tuberc Lung Dis. 1990 Jun-Sep;65(2-3):86–91. [PubMed] [Google Scholar]
  8. Heifets L. B., Flory M. A., Lindholm-Levy P. J. Does pyrazinoic acid as an active moiety of pyrazinamide have specific activity against Mycobacterium tuberculosis? Antimicrob Agents Chemother. 1989 Aug;33(8):1252–1254. doi: 10.1128/aac.33.8.1252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. KONNO K., KURZMANN R., BIRD K. T. The metabolism of nicotinic acid in Mycobacteria: a method for differentiating tubercle bacilli of human origin from other Mycobacteria. Am Rev Tuberc. 1957 Apr;75(4):529–537. doi: 10.1164/artpd.1957.75.4.529. [DOI] [PubMed] [Google Scholar]
  10. Kilburn J. O., Kubica G. P. Reagent-impregnated paper strips for detection of niacin. Am J Clin Pathol. 1968 Oct;50(4):530–532. doi: 10.1093/ajcp/50.4_ts.530. [DOI] [PubMed] [Google Scholar]
  11. Konno K., Feldmann F. M., McDermott W. Pyrazinamide susceptibility and amidase activity of tubercle bacilli. Am Rev Respir Dis. 1967 Mar;95(3):461–469. doi: 10.1164/arrd.1967.95.3.461. [DOI] [PubMed] [Google Scholar]
  12. Lecoeur H. F., Truffot-Pernot C., Grosset J. H. Experimental short-course preventive therapy of tuberculosis with rifampin and pyrazinamide. Am Rev Respir Dis. 1989 Nov;140(5):1189–1193. doi: 10.1164/ajrccm/140.5.1189. [DOI] [PubMed] [Google Scholar]
  13. MACKANESS G. B. The intracellular activation of pyrazinamide and nicotinamide. Am Rev Tuberc. 1956 Nov;74(5):718–728. doi: 10.1164/artpd.1956.74.5.718. [DOI] [PubMed] [Google Scholar]
  14. MALONE L., SCHURR A., LINDH H., McKENZIE D., KISER J. S., WILLIAMS J. H. The effect of pyrazinamide (aldinamide) on experimental tuberculosis in mice. Am Rev Tuberc. 1952 May;65(5):511–518. [PubMed] [Google Scholar]
  15. McClatchy J. K., Tsang A. Y., Cernich M. S. Use of pyrazinamidase activity on Mycobacterium tuberculosis as a rapid method for determination of pyrazinamide susceptibility. Antimicrob Agents Chemother. 1981 Oct;20(4):556–557. doi: 10.1128/aac.20.4.556. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. McDERMOTT W., TOMPSETT R. Activation of pyrazinamide and nicotinamide in acidic environments in vitro. Am Rev Tuberc. 1954 Oct;70(4):748–754. doi: 10.1164/art.1954.70.4.748. [DOI] [PubMed] [Google Scholar]
  17. Tarnok I., Pechmann H., Krallmann-Wenzel U., Röhrscheidt E., Tarnok Z. Nikotinamidase und die sogenannte Pyrazinamidase in Mycobakterien; gekoppeltes Auftreten der beiden Enzymaktivitäten. Zentralbl Bakteriol Orig A. 1979 Jul;244(2-3):302–308. [PubMed] [Google Scholar]
  18. Wayne L. G. Simple pyrazinamidase and urease tests for routine identification of mycobacteria. Am Rev Respir Dis. 1974 Jan;109(1):147–151. doi: 10.1164/arrd.1974.109.1.147. [DOI] [PubMed] [Google Scholar]
  19. YEAGER R. L., MUNROE W. G. C., DESSAU F. I. Pyrazinamide (aldinamide) in the treatment of pulmonary tuberculosis. Am Rev Tuberc. 1952 May;65(5):523–546. [PubMed] [Google Scholar]
  20. Young W. D., Jr, Maslansky A., Lefar M. S., Kronish D. P. Development of a paper strip test for detection of niacin produced by mycobacteria. Appl Microbiol. 1970 Dec;20(6):939–945. doi: 10.1128/am.20.6.939-945.1970. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES