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A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis

Abstract

Mycobacterium tuberculosis, which causes tuberculosis, is the greatest single infectious cause of mortality worldwide, killing roughly two million people annually1. Estimates indicate that one-third of the world population is infected with latent M. tuberculosis2. The synergy between tuberculosis and the AIDS epidemic3,4,5, and the surge of multidrug-resistant clinical isolates of M. tuberculosis have reaffirmed tuberculosis as a primary public health threat. However, new antitubercular drugs with new mechanisms of action have not been developed in over thirty years. Here we report a series of compounds containing a nitroimidazopyran nucleus that possess antitubercular activity. After activation by a mechanism dependent on M. tuberculosis F420 cofactor, nitroimidazopyrans inhibited the synthesis of protein and cell wall lipid. In contrast to current antitubercular drugs, nitroimidazopyrans exhibited bactericidal activity against both replicating and static M. tuberculosis. Lead compound PA-824 showed potent bactericidal activity against multidrug-resistant M. tuberculosis and promising oral activity in animal infection models. We conclude that nitroimidazopyrans offer the practical qualities of a small molecule with the potential for the treatment of tuberculosis.

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Figure 1: Structure of Metronidazole, CGI-17341 and PA-824.
Figure 2: NAP activity on static MTB maintained in microaerophilic culture.
Figure 3: In vivo activity of PA-824 in murine and guinea pig models of tuberculosis infection.
Figure 4: Effects of NAP on protein and lipid synthesis.
Figure 5: Metabolism of 14C-labelled PA-824 BCG cells were incubated with labelled drug, and labelled metabolites were recovered from disrupted cells and analysed by TLC.

References

  1. Dye, C., Scheele, S., Dolin, P., Pathania, V. & Raviglione, M. C. Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. J. Am. Med. Ass. 282, 677–686 (1999).

    CAS  Article  Google Scholar 

  2. Bloom, B. R. & Small, P. M. The evolving relation between humans and Mycobacterium tuberculosis. N. Engl. J. Med. 338, 677–678 (1998).

    CAS  Article  PubMed  Google Scholar 

  3. Kaufman, S. & van Embden, J. Tuberculosis: a neglected disease strikes back. Trends Microbiol. 1, 2– 5 (1993).

    Article  Google Scholar 

  4. Bloom, B. R. & Murray, C. J. Tuberculosis: commentary on a reemergent killer. Science 257, 1055– 1064 (1992).

    ADS  CAS  Article  PubMed  Google Scholar 

  5. Fischl, M. A. et al. Clinical presentation and outcome of patients with HIV infection and tuberculosis caused by multiple-drug-resistant bacilli. Ann. Int. Med. 117, 184–190 ( 1992).

    CAS  Article  PubMed  Google Scholar 

  6. Agrawal, K. C. et al. Potential radiosensitizing agents. Dinitroimidazoles. J. Med. Chem. 22, 593–586 (1979).

    Article  Google Scholar 

  7. Nagarajan, K., Shankar, R. G., Rajappa, S., Shenoy, S. J. & Costa-Pereira, R. Nitroimidazoles XXI 2,3-dihydro-6-nitroimidazo [2,1-b] oxazoles with antitubercular activity. Eur. J. Med. Chem. 24, 631–633 ( 1989).

    CAS  Article  Google Scholar 

  8. Walsh, J. S. et al. Structural alterations that differentially affect the mutagenic and antitrichomonal activities of 5-nitroimidazoles. J. Med. Chem. 30, 150–156 ( 1987).

    CAS  Article  PubMed  Google Scholar 

  9. Ashtekar, D. R. et al. In vitro and in vivo activities of the nitroimidazole CGI 17341 against Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 37, 183–186 ( 1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Wayne, L. G. & Sramek, H. A. Metronidazole is bactericidal to dormant cells of Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 38, 2054–2054 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Hickey, M. J. et al. Luciferase in vivo expression technology: use of recombinant mycobacterial reporter strains to evaluate antimycobacterial activity in mice. Antimicrob. Agents Chemother. 40, 400– 407 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Yuan, Y. & Barry, C. E. A common mechanism for the biosynthesis of methoxy and cyclopropyl mycolic acids in Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 93, 12828– 12833 (1996).

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Samuelson, J. Why metronidazole is active against both bacteria and parasites. Antimicrob. Agents Chemother. 43, 1533–1541 ( 1999).

  14. Edwards, D. I. Mechanism of antimicrobial action of metronidazole. J. Antibicrob. Chemother. 5, 499–502 (1979).

  15. Lisitsyn, N. & Lisitsyn, N. W. M. Cloning the differences between two complex genomes. Science 259, 946– 951 (1993).

    ADS  CAS  Article  PubMed  Google Scholar 

  16. Cole, S. T. et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393, 537–544 (1998).

    ADS  CAS  Article  PubMed  Google Scholar 

  17. Purwantini, E. & Daniels, L. Purification of a novel coenzyme F420-dependent glucose-6-phosphate dehydrogenase from Mycobacterium smegmatis. J. Bacteriol. 178, 2861–2866 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Purwantini, E. & Daniels, L. Molecular analysis of the gene encoding F420-dependent glucose-6-phosphate dehydrogenase from Mycobacterium smegmatis. J. Bacteriol. 180, 2212–2219 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Barry, C. E. et al. Mycolic acids: structure, biosynthesis and physiological functions. Prog. Lipid Res. 37, 143– 179 (1998).

    ADS  CAS  Article  PubMed  Google Scholar 

  20. Yuan, Y., Zhu, Y., Crane, D. D. & Barry, C. E. The effect of oxygenated mycolic acid composition on cell wall function and macrophage growth in Mycobacterium tuberculosis. Mol. Microbiol. 29, 1449–1458 (1998).

    CAS  Article  PubMed  Google Scholar 

  21. Holt, J. G., Krieg, N. R., Sneath, P. H. A., Staley, J. T. & Williams, S. T. in Bergey's Manual of Determinative Bacteriology 9th edn 597 (Williams and Wilkins, Baltimore, 1994).

    Google Scholar 

  22. Arain, T. M., Resconi, A. E., Hickey, M. J. & Stover, C. K. Bioluminescence screening in vitro (Bio-Siv) assays for high-volume antimycobacterial drug discovery. Antimicrob. Agents Chemother. 40, 1536–1541 ( 1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. van Embden, J. D. et al. Strain identification of Mycobacterium tuberculosis by DNA fingerprinting: recommendations for a standardized methodology. J. Clin. Microbiol. 31, 406–409 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Smith, D. W., Balasubramanian, V. & Wiegeshaus, E. H. A guinea pig model of experimental airborne tuberculosis for the evaluation of the response to chemotherapy: the effect on bacilli in the initial phase of treatment. Tubercle 72, 223–231 (1991).

    CAS  Article  PubMed  Google Scholar 

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Correspondence to C. Kendall Stover.

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Stover, C., Warrener, P., VanDevanter, D. et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 405, 962–966 (2000). https://doi.org/10.1038/35016103

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