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JAC Advance Access originally published online on October 16, 2003
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Journal of Antimicrobial Chemotherapy (2003) 52, 801-808
© 2003 The British Society for Antimicrobial Chemotherapy

Antimycobacterial activity of 2-methyl-adenosine

Esther W. Barrow1, Louise Westbrook2, Namita Bansal3, William J. Suling2, Joseph A. Maddry3, William B. Parker2 and William W. Barrow1,*

1 Mycobacteriology Research Unit, Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078; 2 Biochemistry and Molecular Biology and 3 Organic Chemistry, Southern Research Institute, Birmingham, AL 35205, USA

Received 12 June 2003; returned 19 July 2003; revised 28 July 2003; accepted 15 August 2003

Objectives: The aims of this study were to assess the in vitro activity of 2-methyl-adenosine against Mycobacterium tuberculosis and evaluate, and to intracellular efficacy, and to evaluate its effectiveness against M. tuberculosis in a persistent state model and examine its potential mechanism of action.

Methods: In vitro activity was determined by means of a colorimetric microdilution broth assay. Intracellular activity was assessed with a Mono Mac 6 human monocytic cell line. A hypoxic shift-down model was used to evaluate the effect of 2-methyl-adenosine on M. tuberculosis in a persistent state. Mechanism-of-action studies were conducted by examining the effect of 2-methyl-adenosine on the uptake of appropriate radiolabelled precursors into respective mycobacterial macromolecular components.

Results: Studies confirmed the in vitro activity of 2-methyl-adenosine against M. tuberculosis and demonstrated intracellular efficacy against M. tuberculosis within macrophages. 2-Methyl-adenosine was able to significantly affect the viability of M. tuberculosis in a hypoxic shift-down model previously described to simulate the persistent state that results during tuberculosis. Mechanism-of-action studies revealed that the immediate inhibitory effects of 2-methyl-adenosine were associated with protein and DNA synthesis and not RNA synthesis.

Conclusions: Results indicate that 2-methyl-adenosine, or similar derivatives, might be effective against M. tuberculosis infections during latency. This information should be helpful in understanding purine metabolism of M. tuberculosis and also the metabolic activity of this important human pathogen in the persistent state.

Keywords: mycobacterium, nucleoside analogues, MICs

* Corresponding author. Tel: +1-405-744-1842; E-mail: barrowb{at}okstate.edu


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