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

Author

Listed:
  • C. Kendall Stover

    (PathoGenesis Corporation)

  • Paul Warrener

    (PathoGenesis Corporation)

  • Donald R. VanDevanter

    (PathoGenesis Corporation)

  • David R. Sherman

    (School of Public Health and Community Medicine, University of Washington)

  • Taraq M. Arain

    (PathoGenesis Corporation)

  • Michael H. Langhorne

    (PathoGenesis Corporation)

  • Scott W. Anderson

    (PathoGenesis Corporation)

  • J. Andrew Towell

    (PathoGenesis Corporation)

  • Ying Yuan

    (PathoGenesis Corporation)

  • David N. McMurray

    (Texas A&M University Health Science Center, Room 463 Reynolds Medical Building College Station)

  • Barry N. Kreiswirth

    (Tuberculosis Center, Public Health Research Institute)

  • Clifton E. Barry

    (Tuberculosis Research Section, Laboratory of Host Defenses, NIAID, NIH, Twinbrook 2, Room 239)

  • William R. Baker

    (PathoGenesis Corporation)

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.

Suggested Citation

  • C. Kendall Stover & Paul Warrener & Donald R. VanDevanter & David R. Sherman & Taraq M. Arain & Michael H. Langhorne & Scott W. Anderson & J. Andrew Towell & Ying Yuan & David N. McMurray & Barry N. K, 2000. "A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis," Nature, Nature, vol. 405(6789), pages 962-966, June.
    • Handle: RePEc:nat:nature:v:405:y:2000:i:6789:d:10.1038_35016103
    DOI: 10.1038/35016103
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    Cited by:

    1. Filipa Mota & Camilo A. Ruiz-Bedoya & Elizabeth W. Tucker & Daniel P. Holt & Patricia Jesus & Martin A. Lodge & Clara Erice & Xueyi Chen & Melissa Bahr & Kelly Flavahan & John Kim & Mary Katherine Bro, 2022. "Dynamic 18F-Pretomanid PET imaging in animal models of TB meningitis and human studies," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    2. Katherine A. Abrahams & Sarah M. Batt & Sudagar S. Gurcha & Natacha Veerapen & Ghader Bashiri & Gurdyal S. Besra, 2023. "DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid," Nature Communications, Nature, vol. 14(1), pages 1-10, December.

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